Compositions for the treatment of gastrointestinal inflammation

ABSTRACT

Provided herein are methods for treating, preventing or alleviating the symptoms of and inflammation associated with inflammatory diseases and conditions of the gastrointestinal tract, for example, those involving the esophagus. Also provided herein are pharmaceutical compositions useful for the methods of the present invention.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.60/987,720, filed Nov. 13, 2007; U.S. Provisional Application No.61/012,012, filed Dec. 6, 2007; U.S. Provisional Application No.61/015,998, filed Dec. 21, 2007; U.S. Provisional Application No.61/019,818, filed Jan. 8, 2008; U.S. Provisional Application No.61/034,941, filed Mar. 7, 2008; U.S. Provisional Application No.61/035,348, filed Mar. 10, 2008; U.S. Provisional Application No.61/054,103, filed May 16, 2008; U.S. Provisional Application No.61/054,104, filed May 16, 2008; U.S. Provisional Application No.61/054,105, filed May 16, 2008; U.S. Provisional Application No.61/054,106, filed May 16, 2008; U.S. Provisional Application No.61/054,107, filed May 16, 2008; and U.S. Provisional Application No.61/090,568, filed Aug. 20, 2008, which applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Esophageal inflammation disorders are gaining increased recognition inboth adults and children. One example is eosinophilic esophagitis (EE orEoE), which is an emerging, and fast-growing disorder characterized byhigh levels of eosinophils in the esophagus, as well as basal zonehyperplasia. EE (EoE) is thought to be provoked, in at least a subset ofpatients, by food allergies or airborne allergen exposure (1-5, 44). EE(EoE) diagnosis is often associated with other hypersensitivitydisorders, including asthma, rhinitis, and other food and aeroallergeninhalant sensitivities (39-40). Diagnosis is often made, e.g., in youngchildren and depends on the finding of 15 to 20 or more to 24 or moreeosinophils per high power field (eos/hpf) within esophageal mucosalbiopsies (6-12).

In parallel with other atopic disorders, the incidence of FE (EoE)appears to be increasing (15, 35). The disorder may present withreflux-like symptoms, pain and dysphagia, clinical symptoms similar tothe presentation of gastroesophageal reflux disease (“GERD”) (42).Symptoms of EE (EoE) include, for example, abdominal pain, chest pain,choking, difficulty swallowing, failure to thrive, nausea, reflux notrelieved by standard anti-flux therapy, skin rash or hives, vomiting,and weight loss. In one series, 15% of EE (EoE) patients had concurrentdevelopmental delay (45).

Although EE (EoE) is becoming more frequently diagnosed throughoutdeveloping countries (7, 8, 13-16) many aspects of the disease remainunclear including its etiology, natural history and optimal therapy.Symptoms of EE (EoE) often mimic those of GERD and include vomiting,dysphagia, pain and food impaction (8, 14, 17-20). However, treatment ofEE (EoE) and GERD differ and it is important to distinguish betweenthem, particularly as untreated EE (EoE) may be associated withesophageal narrowing in 10-30% of cases (14, 18, 20, 21). The overlap ofGERD and EE (EoE) symptoms is common; failure to respond to high PPIGERD treatment may be one diagnostic guideline for EE (EoE) (42). Thecommon occurrence regarding misdiagnosis of EE (EoE) for GERD oftenresults in delayed treatment for patients with EE. (42).

Long term systemic steroid therapy can result in significant secondaryside effects on growth and bone development. Although treatment withanti-IL-5 monoclonal antibody has been reported to be successful in EE,this therapy is currently not approved for use in children (36).

Current treatments include elimination diets (22, 23), and elementalformulas (2, 24). Identifying true inciting food allergens can bedifficult and elemental formulas are often unpalatable, thereby makingdietary interventions complicated (1, 22). Improvised puff and swallowtechniques may be difficult for patients, especially smaller children,and especially children with developmental delays, to performefficiently. This may result in a less than effective dose of a topicalsteroid being delivered to the esophagus.

SUMMARY OF THE INVENTION

Provided in certain embodiments herein is an oral pharmaceuticalcomposition comprising a corticosteroid, and a mucoadhesive agent. Inspecific embodiments, the oral pharmaceutical composition is a stableoral pharmaceutical composition, being both chemically and physicallystable for at least one month (e.g., under ambient conditions, or underinert conditions, such as under an inert gas or vacuum). In someembodiments, the oral pharmaceutical composition further comprises aliquid vehicle. In certain embodiments, the corticosteroid is atopically active corticosteroid. In some embodiments, the corticosteroidis budesonide. In other embodiments, the corticosteroid is fluticasonepropionate.

In some embodiments, when an oral pharmaceutical composition describedherein is administered to an esophagus, e.g., by oral administration, atleast 50%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the oralpharmaceutical composition adheres to or resides upon the esophagus forat least 15 seconds, or 1 minute. In certain embodiments, when an oralpharmaceutical composition described herein is administered to theesophagus, e.g., by oral administration, at least 50%, 20%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, or 1% of the corticosteroid adheres to orresides upon the esophagus for at least 15 seconds, or at least 1minute. In some embodiments, at least 50%, 20%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, or 1% of the corticosteroid adheres to or is absorbed by theesophagus at least 15 seconds, or at least 1 minute after application ofan oral pharmaceutical composition described herein is administered tothe esophagus, e.g., by oral administration. In certain embodiments,administration of the oral pharmaceutical composition to the esophagusincludes orally administering and/or swallowing at least part of theoral pharmaceutical composition or dose of the oral pharmaceuticalcomposition.

In certain embodiments, the weight percent of an oral pharmaceuticalcomposition described herein that adheres to or resides upon theesophagus 15 seconds or 1 minute after application to the esophagus,e.g., by oral administration, is greater than the weight percent of acontrol composition that adheres to or resides upon the esophagus 15seconds or 1 minute after application to the esophagus of the controlcomposition, e.g., by oral administration. In some embodiments, theamount of corticosteroid that adheres to or resides upon the esophagus15 seconds or 1 minute after application to the esophagus, e.g., by oraladministration, of an oral pharmaceutical composition described hereinis greater than the amount of corticosteroid that adheres to or isabsorbed by the esophagus 15 seconds or 1 minute after application tothe esophagus, e.g., by oral administration, of a control composition.In some embodiments, the amount of corticosteroid that adheres to or isabsorbed by the esophagus 15 seconds or 1 minute after application tothe esophagus, e.g., by oral administration, of an oral pharmaceuticalcomposition described herein is greater than the amount ofcorticosteroid that adheres to or is absorbed by the esophagus 15seconds or 1 minute after application to the esophagus, e.g., by oraladministration of a control composition. In specific embodiments, acontrol composition described herein comprises the same corticosteroidin the same amount as present in the oral pharmaceutical composition,and comprises about 4 mL of an aqueous formulation (e.g., a Pulmicort®formulation) and 10 packs of Splenda® (distributed by McNeilNutritionals, LLC Fort Washington, Pa. 19034-2299) for every 0.5 mg ofcorticosteroid.

In certain embodiments, the mucoadhesive agent described herein is, byway of non-limiting example, a mucoadhesive polysaccharide, a carbopol.Carbopols include, by way of non-limiting example, a cross-linkedacrylic acid polymer, Carbopol Ultrez and Carbopol 974P. In someembodiments, the mucoadhesive agent described herein is, by way ofnon-limiting example an alginate. In specific embodiments, the alginateis, by way of non-limiting example, sodium alginate LF120 and/or sodiumalginate H120L. In certain embodiments, the mucoadhesive agent comprisesone or more maltodextrin. In specific embodiments, the maltodextrin doesnot substantially increase the viscosity of the oral pharmaceuticalcomposition (e.g., compared to an otherwise identical compositionlacking the maltodextrin). In further or alternative embodiments, themaltodextrin is chosen for its mucoadhesive properties (e.g., itsability to impart mucoadhesive character upon the oral pharmaceuticalcomposition). In some embodiments, the oral pharmaceutical compositioncomprises a second maltodextrin that increases the viscosity of the oralpharmaceutical composition (e.g., compared to an otherwise identicalcomposition lacking the second maltodextrin). In specific embodiments,the second maltodextrin does not substantially affect the mucoadhesivecharacteristic of the pharmaceutical composition (e.g., compared to anotherwise identical composition lacking the second maltodextrin).

In some embodiments, a mucoadhesive agent utilized in an oralpharmaceutical composition disclosed herein imparts an increasedviscosity upon the oral pharmaceutical composition (e.g., compared to anotherwise identical composition lacking the mucoadhesive agent). Inother embodiments, the mucoadhesive agent does not substantiallyincrease the viscosity of the oral pharmaceutical composition (e.g.,compared to an otherwise identical composition lacking the mucoadhesiveagent).

In certain embodiments, an oral pharmaceutical composition describedherein further comprises a second mucoadhesive agent. In further oralternative embodiments, an oral pharmaceutical composition describedherein further comprises a viscosity enhancing agent.

Also provided herein is a method of treating, preventing or alleviatinggastrointestinal inflammation or symptoms of gastrointestinalinflammation in an individual comprising orally administering to saidindividual any pharmaceutical composition described herein. In certainembodiments, the gastrointestinal inflammation is, by way ofnon-limiting example, esophageal inflammation. In specific embodiments,the individual has been diagnosed with eosinophilic esophagitis, aninflammatory bowel disease involving the esophagus, Crohn's disease,proximal gastrointestinal pathology (e.g., in individuals suffering fromhypofunctioning gallbladder), eosinophilic gastrointestinalinflammation, celiac disease, eosinophilic duodenitis, duodenaleosinophilia, functional dyspepsia, intermediate esophagitis, epithelialhyperplasia, basal cell hyperplasia, elongated papillae, dilated vesselsin papillae, fungal esophagitis (e.g., Candida, turolopsis, histoplasmaAspergillus, etc.), viral esophagitis (e.g., HSV, CMV, V2V), bacterialesophagitis (e.g., tuberculosis, actinomycosis, syphlis), corrosiveesophagitis, radiation esophagitis, chemotherapy esophagitis, graft vs.host disease, a skin disease with esophageal involvement (e.g., bullouspemphigoid, pemphigus vulgaris, epidermolysis bollosa, Stevens-Johnsonsyndrome), Behçet's disease, sarcoidosis, idiopathic esophagitis,eosinophilic gastritis, Menetrier's disease, parasitic gastritis,lymphocytic esophagitis, inflammatory bowel disease-associatedesophagitis, parasitic gastritis, esophageal inflammation secondary tocaustic/irritant ingestion, persistent/recurrent esophageal stricturesof any cause and including caustic/irritant ingestion, pill-inducedesophagitis, systemic diseases, congenital diseases, post-surgeryinflammation, or gastro enteritis. In more specific embodiments, theindividual has eosinophilic esophagitis. In other specific embodiments,individual has been diagnosed with gastroesophageal reflux disease(GERD), nonerosive reflux disease (NERD), or erosive esophagitis. Insome embodiments, the gastrointestinal inflammation is, by way ofnon-limiting example, inflammation of the stomach and/or the smallintestines, e.g., gastro enteritis.

In certain embodiments, a pharmaceutical composition described comprisesor a method described herein comprises administering (e.g., per day orper dose) to an individual about 0.1 mg to about 20 mg corticosteroid,about 0.1 mg to about 10 mg corticosteroid, about 0.3 mg to about 5 mgcorticosteroid, about 0.3 mg to about 4 mg corticosteroid, about 1 toabout 2 mg corticosteroid, about 2 to about 3 mg corticosteroid, orabout 0.25 to about 2.5 mg of corticosteroid.

In some embodiments, a method described herein comprises administering acomposition described herein to a child. In specific embodiments, thechild less than 19 years old, less than 16 years old, less than 12 yearsold, less than 8 years old, less than 6 years old, less than 4 years oldor less than 2 years old. In some embodiments, a method described hereincomprises administering a composition described herein to an adult.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 illustrates the percent amount of composition present in theesophagus as a function of time following oral administration (bymeasuring the amount of radiolabel present in the esophagus).

DETAILED DESCRIPTION OF THE INVENTION

In certain embodiments, the present invention is directed to methods andpharmaceutical compositions for treating, preventing or alleviating thesymptoms of and inflammation associated with inflammatory diseasesinvolving the gastrointestinal tract, including the esophagus, stomachand/or digestive tract. Provided herein are methods of treating,preventing or alleviating, for example, esophageal inflammation in anindividual. In certain embodiments, these methods comprise orallyadministering to said individual a corticosteroid in association with atleast one excipient to increase the mucoadhesive characteristic of thecomposition (a mucoadhesive agent). In some embodiments, provided hereinis an pharmaceutical composition comprising a corticosteroid and amucoadhesive agent. In certain embodiments, the pharmaceuticalcomposition further comprises a liquid vehicle. In further oralternative embodiments, the pharmaceutical composition is suitable fororal administration. In some embodiments, the increased mucoadhesivecharacteristic of the composition allows the composition to be incontact with the esophagus for an extended period of time followingadministration.

In certain embodiments, the excipient or excipients chosen increase theinteraction of the composition with the surface of the gastrointestinaltract (e.g., the mucosa and/or epithelium of the gastrointestinal tractor of a specific site of the gastrointestinal tract, such as theesophagus) by at least 1.02 fold, by at least 1.05-fold, by at least 1.1fold, by at least 1.2 fold, by at least 1.25-fold, by at least 1.5-fold,by at least 2-fold, by at least 3-fold, by at least 4-fold or by atleast 5-fold. In certain embodiments, the increased interaction of thecomposition is an at least 1.02 fold, by at least 1.05-fold, by at least1.1 fold, by at least 1.2 fold, by at least 1.25-fold, by at least1.5-fold, by at least 2-fold, by at least 3-fold, by at least 4-fold orby at least 5-fold of interaction of the composition with the esophagusthat occurs following passing of the bolus of the composition beingswallowed. In certain embodiments, these increases are measured andcompared to the measure of an otherwise similar composition lacking theexcipient or excipients that increase the interaction of the compositionwith the surface of the gastrointestinal tract. In certain instances,increased interaction of the composition is measured as a function ofthe amount of composition present in a selected or targeted portion ofthe gastrointestinal tract, such as the esophagus (e.g., as measuredafter the bolus has passed through the esophagus, which may be 5seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 11seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds, or the likefollowing initial swallowing of at least a portion of the composition).In specific instances, the amount of composition present in theesophagus is measured in any suitable manner, e.g., by radiolabeling thecomposition and measuring the amount of the composition in the esophagusutilizing gamma scintigraphy. An increase in the interaction of thecomposition with the surface of the gastrointestinal tract (e.g., thesurface of the esophagus) may be measured by measuring the retentiontime of the material along a length of a surface of the gastrointestinaltract (e.g., the surface of the esophagus), wherein the retention timeis increased in the presence of the excipients as compared to itsabsence. In another embodiment an increased interaction may be measuredby the decrease in physiological manifestations or symptoms of thedisease or ailment to be treated, including a decrease in totaleosinophil counts in a target sample.

In one aspect of the invention, the use of the excipients may act todecrease the quantity of active agents needed to elicit a response inthe absence of the excipients. In some embodiments, the excipients maydecrease the amount of corticosteroid used. Accordingly, thecompositions provided herein may provide an additional advantage ofdecreasing the amount of active agent needed to treat subjects afflictedwith inflammatory diseases involving the gastrointestinal tract,including the esophagus, stomach and/or digestive tract.

In certain embodiments, an active is utilized in an pharmaceuticalcomposition described herein that would benefit from an increasedinteraction with a surface of the gastrointestinal tract (e.g., atopically active corticosteroid).

An individual suitable for treatment with the compositions disclosedherein may, for example, have been diagnosed with a disease or conditionincluding, but not limited to, eosinophilic esophagitis, inflammatorybowel diseases involving the esophagus, eosinophilic gastroenteritis,Crohn's disease, celiac disease, proximal gastrointestinal pathology(e.g., in individuals suffering from hypofunctioning gallbladder),eosinophilic gastrointestinal inflammation, celiac disease, eosinophilicduodenitis, duodenal eosinophilia, functional dyspepsia, intermediateesophagitis, epithelial hyperplasia, basal cell hyperplasia, elongatedpapillae, dilated vessels in papillae, fungal esophagitis (e.g.,Candida, turolopsis, histoplasma Aspergillus, etc.), viral esophagitis(e.g., HSV, CMV, V2V), bacterial esophagitis (e.g., tuberculosis,actinomycosis, syphlis), corrosive esophagitis, radiation esophagitis,chemotherapy esophagitis, graft vs. host disease, a skin disease withesophageal involvement (e.g., bullous pemphigoid, pemphigus vulgaris,epidermolysis bollosa, Stevens-Johnson syndrome), Behçet's disease,sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier'sdisease, parasitic gastritis, lymphocytic esophagitis, inflammatorybowel disease-associated esophagitis, parasitic gastritis, esophagealinflammation secondary to caustic/irritant ingestion,persistent/recurrent esophageal strictures of any cause and includingcaustic/irritant ingestion, pill-induced esophagitis, systemic diseases,congenital diseases, post-surgery inflammation, or gastro enteritis. Thecomposition may also be used in treating other gastrointestinaldisorders, including stomach and duodenal ulcers, hyperactive acidicdischarge disorders, such as Zollinger-Ellison syndrome and laryngealdisorders.

An individual suitable for treatment with the compositions disclosedherein may, for example, have been diagnosed with a disease or conditionincluding, but not limited to, eosinophilic esophagitis, inflammatorybowel diseases involving the esophagus, Crohn's disease, celiac disease,proximal gastrointestinal pathology (e.g., in individuals suffering fromhypofunctioning gallbladder), eosinophilic gastrointestinalinflammation, celiac disease, eosinophilic duodenitis, duodenaleosinophilia, functional dyspepsia, intermediate esophagitis, epithelialhyperplasia, basal cell hyperplasia, elongated papillae, dilated vesselsin papillae, fungal esophagitis (e.g., Candida, turolopsis, histoplasmaAspergillus, etc.), viral esophagitis (e.g., HSV, CMV, V2V), bacterialesophagitis (e.g., tuberculosis, actinomycosis, syphlis), corrosiveesophagitis, radiation esophagitis, chemotherapy esophagitis,eosinophilic gastric outlet obstruction and related inflammation, graftvs. host disease, a skin disease with esophageal involvement (e.g.,bullous pemphigoid, pemphigus vulgaris, epidermolysis bollosa,Stevens-Johnson syndrome), Behçet's disease, sarcoidosis, idiopathicesophagitis, eosinophilic gastritis, Menetrier's disease, parasiticgastritis, lymphocytic esophagitis, inflammatory boweldisease-associated esophagitis, parasitic gastritis, esophagealinflammation secondary to caustic/irritant ingestion,persistent/recurrent esophageal strictures of any cause and includingcaustic/irritant ingestion, pill-induced esophagitis, systemic diseases,congenital diseases, post-surgery inflammation, or gastro enteritis. Thecomposition may also be used in treating individuals diagnosed withother gastrointestinal disorders, including stomach and duodenal ulcers,hyperactive acidic discharge disorders, such as Zollinger-Ellisonsyndrome and laryngeal disorders. In some embodiments, the compositionsor methods disclosed herein are used in methods of treating individualsdiagnosed with other gastrointestinal disorders, including, by way ofnon-limiting example, Barrett's Esophagus, gastroesophageal refluxdisease (GERD), nonerosive reflux disease (NERD), or erosiveesophagitis. In some embodiments, the methods of treating, preventing oralleviating inflammation or symptoms of inflammation include methods oftreating any of the gastrointestinal disorders described herein. Incertain embodiments, these methods comprise orally administering to saidindividual a corticosteroid-containing compositions described herein.

Provided herein are methods for treating, preventing and alleviating anychronic inflammatory or malignant state that involves thegastrointestinal tract, such as the esophagus, and responds to steroidtherapy. The methods and compositions of the present invention areuseful, for example, for treating, preventing and alleviatinginflammation and/or symptoms and associated with eosinophilicesophagitis, inflammatory bowel diseases involving the esophagus,Crohn's disease, celiac disease, proximal gastrointestinal pathology(e.g., in individuals suffering from hypofunctioning gallbladder),eosinophilic gastrointestinal inflammation, celiac disease, eosinophilicduodenitis, duodenal eosinophilia, functional dyspepsia, intermediateesophagitis, epithelial hyperplasia, basal cell hyperplasia, elongatedpapillae, dilated vessels in papillae, fungal esophagitis (e.g.,Candida, turolopsis, histoplasma Aspergillus, etc.), viral esophagitis(e.g., HSV, CMV, V2V), bacterial esophagitis (e.g., tuberculosis,actinomycosis, syphlis), corrosive esophagitis, radiation esophagitis,chemotherapy esophagitis, graft vs. host disease, a skin disease withesophageal involvement (e.g., bullous pemphigoid, pemphigus vulgaris,epidermolysis bollosa, Stevens-Johnson syndrome), Behçet's disease,sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier'sdisease, parasitic gastritis, lymphocytic esophagitis, inflammatorybowel disease-associated esophagitis, parasitic gastritis, esophagealinflammation secondary to caustic/irritant ingestion,persistent/recurrent esophageal strictures of any cause and includingcaustic/irritant ingestion, pill-induced esophagitis, systemic diseases,congenital diseases, Epidermolysis bullosa, post-surgery inflammation,and gastro enteritis. The present methods are also useful for treating,preventing or alleviating symptoms and/or inflammation associated withother diseases or conditions of the gastrointestinal tract, for example,the upper gastrointestinal tract, where it is beneficial to target aparticular target site, rather than provide systemic therapy. Alsoprovided herein are pharmaceutical compositions useful in the methods ofthe present application. As used herein, inflammation and/or symptomsassociated with a disorder or disease disclosed herein includesinflammation and/or symptoms associated with, caused by and/or resultingfrom the disorder or disease.

As used herein, unless otherwise stated, the use of the terms “a”, “an”and “the” include both singular and multiple embodiments. As usedherein, the term “individual” includes any animal. In some embodiments,the animal is a mammal. In certain embodiments, the mammal is a human.In specific embodiments, the human is an adult. In other embodiments,the human is a child (e.g., a child under 12 or a child under 6). Incertain embodiments, the human is an infant. As used herein, the phrase“method of treating” or “method for treating” can, in some embodiments,encompass methods of preventing, reducing the incidences of, providingprophylactic treatment, treating and alleviating. As used herein, thephrase “an effective amount” and “a therapeutically effective amount” isan amount sufficient to elicit a change in the symptoms of orinflammation associated with gastrointestinal disorders, including butnot limited to esophageal inflammation, eosinophilic esophagitis, GERD,NERD, or erosive esophagitis. As used herein, the term “or” includes“and” and “or”.

As used herein, the phrase “treating inflammatory diseases involving theesophagus” includes treating symptoms of such diseases and treatinginflammation associated with the diseases.

In certain embodiments, as used herein, “substantially” increasing oraffecting includes increasing or deviating, respectively, in an amountof, by way of non-limiting example, about 10%, 5%, 3%, 2%, or 1%.

Methods and Compositions

In certain embodiments, the corticosteroids used in the presentinvention include topical steroids including, for example, budesonide orfluticasone propionate. In some embodiments, corticosteroids areselected from, by way of non-limiting example, aclometasone, amcinomide,beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,clobetasone, clocortolone, cloprednol, cortivazol, deflazacort,deoxycorticosterone, desonide desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, fluclorolone,fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone,fluperolone, fluticasone, fuprednidene, formocortal, halcinonide,halometasone, hydrocortisone aceponate, hydrocortisone buteprate,hydrocortisone butyrate, loteprednol, medrysone, meprednisone,methylprednisolone, methylprednisolone aceponate, mometasone furoate,paramethasone, prednicarbate, prednisone, prednisolone, prednylidene,remexolone, tixocortol, triamcinolone and ulobetasol, and combinations,pharmaceutically acceptable salts and esters thereof. In a specificembodiment, the corticosteroid is budesonide. In another embodiment, thecorticosteroid is an ester of fluticasone, e.g., fluticasone propionate.

Provided herein are methods and pharmaceutical compositions fortreating, preventing or alleviating the symptoms of, and inflammationassociated with, inflammatory diseases of the gastrointestinal tract,including but not limited to the upper gastrointestinal tract (e.g., theesophagus). Also provided herein are methods and pharmaceuticalcompositions for preventing or alleviating the symptoms ofgastrointestinal reflux and an increase in gastric pH, which areassociated with inflammatory diseases of the gastrointestinal tract,including but not limited to the esophagus.

In certain embodiments, a corticosteroid (e.g., budesonide orfluticasone propionate) that is administered in oral form, in aformulation with increased mucoadhesive characteristic, is delivered to,e.g., the esophagus in an effective dose to reduce the inflammation ofthe esophagus.

In one aspect, provided herein is an oral pharmaceutical compositioncomprising a corticosteroid and a mucoadhesive agent. In variousaspects, an exemplary corticosteroid is budesonide,16,17-(butylidenebis(oxy))-11,21-dihydroxy-,(11-β,16-α)-pregna-1,4-diene-3,20-dione, or fluticasone propionate,S-(fluoromethyl)6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate,17 propionate or(6α,11β,16α,17β)-6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioicacid S-(fluoromethyl)ester.

In certain embodiments, pharmaceutical compositions disclosed herein andused herein comprise one or more excipients. Excipients useful hereininclude, by way of non-limiting example, mucoadhesive agents, viscosityenhancing agents, binders, fillers, lubricants, solvents, suspensionagents, flavoring agents, coloring agents, sweeteners, preservatives,antioxidants, buffering agents, humectants, chelating agents,surfactants, and the like.

In certain embodiments, the corticosteroid(s) utilized herein areutilized as particles (e.g., corticosteroid particles suspended ordispersed in an aqueous medium). In specific embodiments, the particlesare microparticles. In some embodiments, the microparticles have a meandiameter of about 0.1 microns to about 50 microns. In specificembodiments, the microparticles have a mean diameter of about 1 micronto about 20 microns. In certain embodiments, at least 95%, at least 98%,or at least 99% of the microparticles have a diameter of less than 10microns.

In some embodiments, a composition or formulation described hereincomprises less than 50% w/w, less than 40% w/w, less than 30% w/w, lessthan 20% w/w, less than 10% w/w, less than 8% w/w, less than 6% w/w,less than 5% w/w, less than 4% w/w, less than 3% w/w, less than 2% w/w,or about 2% w/w, less than 1% w/w, less than 0.5% w/w, less than 0.3%w/w, less than 0.2% w/w, or about 0.2% w/w of undissolved particles. Incertain embodiments, a composition or formulation described herein issubstantially free of non-corticosteroid particles.

In some embodiments, the active corticosteroid described herein issubstituted with another active agent. In certain embodiments, theactive agent is a therapeutic agent that targets the esophagus, e.g.,for treating inflammation of the esophagus, mucusitis, cancer of theesophagus, infections (e.g., bacterial or fungal infections) of theesophagus, esophageal wounds and/or contusions, or the like. In someembodiments, the active agent is a therapeutic agent that issystemically absorbed through the esophagus. In specific embodiments,the therapeutic agent that is systemically absorbed through theesophagus is an agent that is degraded or loses its efficacy in somewhen in the stomach, e.g., a therapeutic peptide.

Mucoadhesive agents to be used herein include, by way of non-limitingexample, a soluble polyvinylpyrrolidone polymer (PVP), a carbopol, acrosslinked poly(acrylic acid) (e.g., Carbopol 974P), a carbomerhomopolymer, a carbomer copolymer, a water-swellable, butwater-insoluble, fibrous, cross-linked carboxy-functional polymer, amucoadhesive polysaccharide (e.g., a hydrophilic polysaccharide gum),one or more maltodextrin, alginate, a cross-linked aliginate gum gel, awater-dispersible polycarboxylated vinyl polymer. In some embodiments,the mucoadhesive agent is a carbopol. In a specific embodiment, themucoadhesive agent is selected from, by way of non-limiting example,Carbopol 974P, Carbopol Ultrez 10, sodium alginate LF120 and sodiumalginate H120L. As used herein, a mucoadhesive agent is an agent thatadheres to a gastrointestinal surface (e.g., either or both of agastrointestinal epithelia or mucosa). In some embodiments, themucoadhesive agent is a cellulose. In specific embodiments, themucoadhesive agent is a carboxymethyl-cellulose (CMC), e.g., sodiumcarboxymethyl-cellulose (NaCMC), microcrystalline cellulose (MCC), or acombination thereof. In one non-limiting example, the mucoadhesive agentis a combination of MCC and CMC (e.g., Avicel RC-591). In someembodiments, the CMC/MCC combination (e.g., Avicel® RC-591) is presentin the composition in an amount of about 1 mg/mL to about 150 mg/mL, 1mg/mL to about 75 mg/mL, or about 5 mg/mL to about 40 mg/mL. In certainembodiments, the CMC/MCC mixed weight ratio is between about 1/99 andabout 99/1, about 20/80 and about 5/95, or about 15/85 and about 10/90.In a specific embodiment, the CMC is NaCMC and the CMC/MCC mixed weightratio is about 11/89.

In specific embodiments, provided herein is a composition comprisingboth a CMC (e.g., a CMC/MCC mixture) and maltodextrin. In certainembodiments, the combination of a CMC (e.g., a CMC/MCC mixture) andmaltodextrin provide an increased residence time on an afflicted ortargeted surface of the gastrointestinal tract (e.g., esophagus), whencompared to a composition having a similar amount of either the CMC(e.g., a CMC/MCC mixture) or maltodextrin alone.

In certain embodiments, the mucoadhesive agent comprises one or moremaltodextrin. In various aspects, the physical characteristics ofmaltodextrins vary depending, e.g., on the dextrose equivalent of thespecific maltodextrin. In certain aspects, the dextrose equivalent of aspecific maltodextrin may affect the viscosity, hygroscopicity,sweetness, humectancy, plasticity, solubility and or mucoadhesiveness ofthe maltodextrin. Thus, in various embodiments, a maltodextrin isselected based on the specific character that is desired to be impartedupon the pharmaceutical composition described herein. In certainembodiments, a maltodextrin is selected that increases the mucoadhesivecharacter of a composition described herein without substantiallyincreasing the viscosity of the composition (e.g., compared to anotherwise identical composition lacking the maltodextrin). In someembodiments, the oral pharmaceutical composition comprises a secondmaltodextrin that increases the viscosity of the oral pharmaceuticalcomposition (e.g., compared to an otherwise identical compositionlacking the second maltodextrin). In specific embodiments, the secondmaltodextrin that does not substantially affect the mucoadhesivecharacteristic of the pharmaceutical composition (e.g., compared to anotherwise identical composition lacking the second maltodextrin).

In some embodiments, the mucoadhesive agent does not substantiallyincrease the viscosity of the oral pharmaceutical composition (e.g.,compared to an otherwise identical composition lacking the mucoadhesiveagent). In further or alternative embodiments, the mucoadhesive agent ischosen for its mucoadhesive properties (e.g., its ability to impartmucoadhesive character upon the oral pharmaceutical composition).

In some embodiments, a mucoadhesive agent utilized in an oralpharmaceutical composition described herein imparts an increasedviscosity upon the oral pharmaceutical composition (e.g., compared to anotherwise identical composition lacking the mucoadhesive agent). Inother embodiments, the mucoadhesive agent does not substantiallyincrease the viscosity of the oral pharmaceutical composition (e.g.,compared to an otherwise identical composition lacking the mucoadhesiveagent).

In some embodiments, at least one mucoadhesive agent is chosen for andused in the pharmaceutical composition so the addition of the at leastone mucoadhesive agent does not substantially increase the viscosity ofthe resulting oral pharmaceutical composition (e.g., compared to anotherwise identical composition lacking the mucoadhesive agent).

In some embodiments, at least two mucoadhesive agents are chosen for andused in the pharmaceutical composition so the addition of the at leasttwo mucoadhesive agents do not substantially increase the viscosity ofthe resulting oral pharmaceutical composition (e.g., compared to anotherwise identical composition lacking the mucoadhesive agents). Insome embodiments, at least one mucoadhesive agent, if taken alone in thepharmaceutical composition would increase the viscosity of thepharmaceutical composition, but taken together with all components inthe pharmaceutical composition, does not substantially increase theviscosity of the resulting oral pharmaceutical composition (e.g.,compared to an otherwise identical composition lacking the at least onemucoadhesive agent).

In some embodiments, the viscosity of the composition is at least about2 centipoise (cP), at least about 5 cP, at least about 10 cP, at leastabout 20 cP, at least about 25 cP, at least about 35 cP, at least about40 cP, at least about 50 cP, at least about 200 cP, or at least about225 cP. In some embodiments, the viscosity of the composition is atleast about 100 cP. In certain embodiments, the viscosity of thecomposition, measured at 25 degrees Celsius, is about 50 cP to about250,000 cP, about 50 cP to about 70,000 cP, about 50 cP to about 25,000cP, about 50 cP to about 10,000 cP, about 50 cP to about 3,000 cP, orabout 50 cP to about 2,000 cP. In one aspect, the viscosity of thecomposition, as measured at 25 degrees Celsius, is from about 25centipoise (cP) to about 800 cP, about 50 cP to about 800, or about 300cP to about 800 cP (e.g., measured by a Brookfield viscometer). Inanother aspect, the viscosity of the composition may range from about100 cP to about 200 cP, about 200 cP to about 300 cP, about 250 cP toabout 600 cP or about 400 cP to about 600 cP. In specific embodiments,the viscosity of the formulation is about 30 cP, about 100 cP, about 200cP, about 300 cP, about 400 cP, about 500 cP, or about 250,000 cP (e.g.,as measured with a Brookfield viscometer at 25 degrees Celsius equippedwith an ultra low adapter).

In some embodiments, the viscosity of the composition is measured atroom temperature (about 25 degrees C.) with a shear rate of about 13.2sec⁻¹. In certain embodiments, provided herein is a composition having aviscosity under such conditions that is at least about 2 centipoise(cP), at least about 5 cP, at least about 10 cP, at least about 20 cP,at least about 25 cP, at least about 30 cP, at least about 35 cP, atleast about 40 cP, at least about 50 cP, at least about 200 cP, at leastabout 225 cP, at least about 250 cP, at least about 300 cP, or at leastabout 400 cP. In some embodiments, the viscosity of the compositionunder such conditions is about 50 cP to about 250,000 cP, about 50 cP toabout 70,000 cP, about 50 cP to about 25,000 cP, about 50 cP to about10,000 cP, about 50 cP to about 3,000 cP, about 50 cP to about 2,000 cP,about 250 cP to about 250,000 cP, about 250 cP to about 70,000 cP, about250 cP to about 25,000 cP, about 250 cP to about 10,000 cP, about 250 cPto about 3,000 cP, or about 250 cP to about 2,000 cP. In one aspect, theviscosity of the composition, as measured at 25 degrees Celsius, is fromabout 25 centipoise (cP) to about 800 cP, about 50 cP to about 800, orabout 300 cP to about 800 cP (e.g., measured by a Brookfieldviscometer). In another aspect, the viscosity of the composition undersuch conditions may range from about 100 cP to about 200 cP, about 200cP to about 300 cP, about 250 cP to about 600 cP or about 400 cP toabout 600 cP. In specific embodiments, the viscosity of the formulationmeasured under such conditions is about 30 cP, about 40 cP, about 100cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, or about250,000 cP.

In some embodiments, the viscosity of the composition is measured atroom temperature (about 25 degrees C.) with a shear rate of about 15sec⁻¹ (e.g., with a gap between the spindle and the sample chamber wallof about 6 mm or greater). In certain embodiments, provided herein is acomposition having a viscosity under such conditions that is at leastabout 150 centipoise (cP), at least about 160 cP, at least about 170 cP,at least about 180 cP, at least about 190 cP, or at least about 200 cP.In some embodiments, the viscosity of the composition under suchconditions is about 150 cP to about 250,000 cP, 160 cP to about 250,000cP, 170 cP to about 250,000 cP, 180 cP to about 250,000 cP, or 190 cP toabout 250,000 cP.

In specific embodiments, the mucoadhesive agent used in any compositiondescribed herein is or comprises at least one maltodextrin.

In certain embodiments, a mucoadhesive agent (e.g., maltodextrin) issubstantially or at least partially dissolved in a liquid vehicle. Insome embodiments, an oral pharmaceutical composition described hereincomprises less than about 0.1 g or less than about 1 g of maltodextrinfor every mL of liquid vehicle in the oral pharmaceutical composition.In certain instances, a composition or formulation described hereincomprises less than 2 g of maltodextrin/mL of composition, less than 1.5g of maltodextrin/mL of composition, less than 1 g of maltodextrin/mL ofcomposition, less than 0.5 g of maltodextrin/mL of composition, lessthan 0.25 g/mL of maltodextrin/mL of composition, about 0.05 g ofmaltodextrin/mL of composition to about 0.5 g of maltodextrin/L ofcomposition, about 0.05 g of maltodextrin/mL of composition to about 0.4g of maltodextrin/mL of composition, about 0.05 g of maltodextrin/mL ofcomposition to about 0.3 g of maltodextrin/mL of composition, about 0.1g of maltodextrin/mL of composition to about 0.5 g of maltodextrin/mL ofcomposition, about 0.1 g of maltodextrin/mL of composition to about 0.4g of maltodextrin/mL of composition, about 0.1 g of maltodextrin/mL ofcomposition to about 0.3 g of maltodextrin/mL of composition, about 0.2g of maltodextrin/mL of composition to about 0.5 g of maltodextrin/mL ofcomposition, about 0.2 g of maltodextrin/mL of composition to about 0.4g of maltodextrin/mL of composition, or about 0.2 g of maltodextrin/mLof composition to about 0.3 g of maltodextrin/ml of composition. In someembodiments, the maltodextrin is substantially dissolved in the liquidvehicle. In certain embodiments, the maltodextrin has a dextroseequivalents (DE) of greater than 4, greater than 5, greater than 10,greater than 11, greater than 12, greater than 13, greater than 14,greater than 15, about 15, about 4 to about 10, about 4 to about 9,about 4 to about 8, about 11 to about 20, about 12 to about 19, about 13to about 18, or about 14 to about 16. In specific embodiments, the firstmaltodextrin has a DE of about 4 to about 10, about 4 to about 9, orabout 4 to about 8 and the second maltodextrin has a DE of about 10 toabout 20, about 12 to about 19, or about 13 to about 18. In someembodiments, at least one maltodextrin utilized in a compositiondescribed herein has a molecular weight high enough to increase thesolubility of a corticosteroid, or to increase the suspendability of acorticosteroid particle.

In some embodiments, mucoadhesive agents are described, for example, inU.S. Pat. Nos. 6,638,521, 6,562,363, 6,509,028, 6,348,502, 6,306,789,5,814,330, and 4,900,552, each of which is hereby incorporated byreference in its entirety.

In one non-limiting example, a mucoadhesive agent can be, by way ofnon-limiting example, at least two particulate components selected fromtitanium dioxide, silicon dioxide, and clay. In some embodiments, whenthe composition is not further diluted with any liquid prior toadministration, the level of silicon dioxide is from about 3% to about15%, by weight of the composition. In certain embodiments, silicondioxide is selected from, by way of non-limiting example, fumed silicondioxide, precipitated silicon dioxide, coacervated silicon dioxide, gelsilicon dioxide, and mixtures thereof. In some embodiments, clay isselected from, by way of non-limiting example, kaolin minerals,serpentine minerals, smectites, illite or mixtures thereof. In certainembodiments, clay is selected from, by way of non-limiting example,laponite, bentonite, hectorite, saponite, montmorillonites or mixturesthereof.

In certain embodiments, the mucoadhesive agent is provided in an amountsufficient to provide exposure of the corticosteroid to a surface of thegastrointestinal tract (e.g., the surface of the esophagus) for asufficient period of time such that the symptoms of and/or inflammationassociated with inflammatory diseases involving the gastrointestinaltract (e.g., of the esophagus, stomach and/or digestive tract) arereduced following administration of the corticosteroid containing oraldosage form as single dose or multiple dose administration.

In some embodiments, the mucoadhesive agent is selected and selected inan amount sufficient to cause the corticosteroid containingpharmaceutical composition to adhere to or resides upon a surface of thegastrointestinal tract (e.g., the surface of the esophagus) for 5seconds, 10 seconds, 15 seconds, 30 seconds, 45 seconds, or 1 minutefollowing application to the surface of the gastrointestinal tract(e.g., the surface of the esophagus), such as by oral administration. Incertain embodiments, the mucoadhesive agent is selected and selected inan amount sufficient to cause the corticosteroid containing compositionto adhere to or reside upon the surface of the gastrointestinal tract(e.g., the surface of the esophagus) for 1.5, 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes after applicationto the surface of the gastrointestinal tract (e.g., the surface of theesophagus). In some embodiments, the amount of corticosteroid containingcomposition that adheres to a surface of the gastrointestinal tract(e.g., the surface of the esophagus) for 5 seconds, 10 seconds, or 0.25,0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40,45, 50, 55 or 60 minutes is at least 1%, at least 2%, at least 3%, atleast 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least9%, at least 10%, at least 15%, at least 20%, at least 30%, at least40%, at least 50%, at least 60%, at least 70%, at least 80%, at least90% or at least 95% by weight after administration to the surface of thegastrointestinal tract (e.g., the surface of the esophagus). In specificembodiments, at least 50% of the pharmaceutical composition adheres toor resides upon the surface of the gastrointestinal tract (e.g., thesurface of the esophagus) for at least 1 or at least 15 minutesfollowing application to the surface of the gastrointestinal tract(e.g., the surface of the esophagus).

In certain embodiments, the mucoadhesive agent is selected and selectedin an amount sufficient to cause the corticosteroid to adhere to and/orbe absorbed at a surface of the gastrointestinal tract (e.g., thesurface of the esophagus) after 5 seconds, 10 seconds, or 0.25, 0.5,0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45,50, 55 or 60 minutes following application to the surface of thegastrointestinal tract (e.g., the surface of the esophagus), such as byoral administration. In some embodiments, the amount of corticosteroidthat adheres to and/or is absorbed at the surface of thegastrointestinal tract (i.e. the sum of the amount that adheres to orresides upon the esophagus and the amount absorbed by the inflamedgastrointestinal) for 5 seconds, 10 seconds, or 0.25, 0.5, 0.75, 1, 1.5,2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60minutes is at least 1%, at least 2%, at least 3%, at least 4%, at least5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, atleast 15%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90% or at least 95% byweight following administration to the surface of the gastrointestinaltract (e.g., the surface of the esophagus). In some embodiments, atleast 50% of the corticosteroid adheres to and/or is absorbed by the gasurface of the gastrointestinal tract (e.g., the surface of theesophagus) at least 1 or at least 15 minutes after administration to thesurface of the gastrointestinal tract (e.g., the surface of theesophagus).

In specific embodiments, following oral administration of a compositiondescribed herein to the esophagus (e.g., following initial swallowing ordrinking of the composition), at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%,9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% by weight ofthe corticosteroid or composition administered is present within theesophagus (e.g., as measured by gamma scintigraphy) after at least 5seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 40seconds, 45 seconds, 50 seconds, or 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10,15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes following applicationof the composition to the esophagus. In certain instances, even smalldifferences (e.g., increases) in adherence times (e.g., residence times)between formulations can result in therapeutically significant orclinically significant results or improvements.

In some embodiments, the weight percent of corticosteroid containingcomposition that adheres to or resides upon the surface of thegastrointestinal tract (e.g., the surface of the esophagus) after 5, 10,15, 30, or 45 seconds or 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,30, 35, 40, 45, 50, 55 or 60 minutes is greater than (e.g., more than1.1×, 1.2×, 1.3×, 1.4×, 1.5×, 2×, 3×, 4×, 5×) the weight percent of acontrol composition that adheres the surface of the gastrointestinaltract (e.g., the surface of the esophagus). In certain embodiments, thecontrol composition contains the same amount of corticosteroid, 4 mL ofaqueous formulation and 10 packs of Splenda® (distributed by McNeilNutritionals, LLC Fort Washington, Pa. 19034-2299) for every 0.5 mg, 1mg, or 2 mg of corticosteroid (e.g., 2 Respules of Pulmicort®, each a 2mL suspension containing 0.25 mg, 0.5 mg, or 1 mg of micronizedbudesonide). For example, in some embodiments for a budesonidecontaining pharmaceutical composition, the control composition contains4 mL Pulmicort® and 10 packets of Splenda®. In some embodiments, thecontrol composition contains the same amount of corticosteroid, 8 mL ofaqueous formulation and 20 packs of Splenda® (packs of Splenda® compriseabout 1 g and are distributed by McNeil Nutritionals, LLC FortWashington, Pa. 19034-2299) for every 0.5 mg, 1 mg, or 2 mg ofcorticosteroid (e.g., 4 Respules of Pulmicort®, each a 2 mL suspensioncontaining 0.25 mg, 0.5 mg, or 1 mg of micronized budesonide). Incertain embodiments, the control composition comprises the same volumeand the same corticosteroid in the same amount as present in the stableoral pharmaceutical composition, and has a viscosity of about 1 cP at25° C. and a shear rate of about 13.2 sec⁻¹ (e.g., Respules ofPulmicort®). Formulations described herein as control compositions arealso contemplated herein. The weight percent of corticosteroidcontaining composition that adheres to or resides upon the surface ofthe gastrointestinal tract (e.g., the surface of the esophagus) may bedetermined by dividing the amount of corticosteroid containingcomposition adhering to the surface of the gastrointestinal tract (e.g.,the surface of the esophagus) by the total amount of corticosteroidcontaining composition that was administered to surface of thegastrointestinal tract (e.g., the surface of the esophagus) andmultiplying the result by 100%. Likewise, the weight percent of controlcomposition that adheres to a surface of the gastrointestinal tract(e.g., the surface of the esophagus) may be determined by dividing theamount of control composition adhering to a surface of thegastrointestinal tract (e.g., the surface of the esophagus) by the totalamount of control composition that was administered to surface of thegastrointestinal tract (e.g., the surface of the esophagus) andmultiplying the result by 100%. In some embodiments, the amount ofcorticosteroid that adheres to or is absorbed by surface of thegastrointestinal tract (e.g., the surface of the esophagus) after 5, 10,15, 30, or 45 seconds or 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,30, 35, 40, 45, 50, 55 or 60 minutes is greater than (e.g., more than1.1×, 1.2×, 1.3×, 1.4×, 1.5×, 2×, 3×, 4×, 5×) a control compositioncontaining the same amount of corticosteroid, e.g., 4 mL of aqueousformulation and 10 packs of Splenda® for every 0.5 mg or 1 mg ofcorticosteroid. One pack of Splenda® contains about one gram of amixture comprising dextrose, maltodextrin and sucralose.

In certain embodiments, a pharmaceutical composition described hereinhas a greater mucoadhesive characteristic and a decreased viscosity whencompared to a control composition containing the same amount ofcorticosteroid. In some embodiments, a pharmaceutical compositiondescribed herein has a substantially similar mucoadhesive characteristicand a decreased viscosity when compared to a control composition. Incertain embodiments, a pharmaceutical composition described hereinadheres to or resides upon a gastrointestinal site (e.g., esophagus) fora length of time greater than or equal to that of a control compositionwhile having a viscosity that is less than or equal to the controlcomposition. In specific embodiments, when the pharmaceuticalcomposition described herein adheres to or resides upon agastrointestinal site (e.g., esophagus) for a length of time equal tothat of a control composition, the viscosity of the pharmaceuticalcomposition described herein is less than that of the controlcomposition. In certain embodiments, the control composition used herecontains 4 mL Pulmicort® (e.g., 0.25 mg or 0.5 mg budesonide per 2 mLdose) and 10 packets of Splenda® (e.g., 4 mL of aqueous formulation and10 packs of Splenda® for every 0.5 mg or 1 mg of corticosteroid). Insome embodiments, the control composition contains the same amount ofcorticosteroid, 8 mL of aqueous formulation and 20 packs of Splenda®(packs of Splenda® comprise about 1 g and are distributed by McNeilNutritionals, LLC Fort Washington, Pa. 19034-2299) for every 0.5 mg, 1mg, or 2 mg of corticosteroid (e.g., 4 Respules of Pulmicort®, each a 2mL suspension containing 0.25 mg, 0.5 mg, or 1 mg of micronizedbudesonide).

In certain embodiments, adherence and/or absorption of a pharmaceuticalcomposition or corticosteroid described herein to a surface of thegastrointestinal tract (e.g., the surface of the esophagus) may bedetermined by scintigraphy or by an assay. In some embodiments, suchdeterminations are performed in vivo or in vitro. In certainembodiments, in vivo scintigraphy may include combining a pharmaceuticalcomposition described herein with a detectable radioisotope,administering the labeled composition to a subject and detecting and/ormeasuring the adherence of the pharmaceutical composition orcorticosteroid to the surface of the gastrointestinal tract (e.g., thesurface of the esophagus) with a device (e.g., camera) that detectsand/or measures radioactivity. In some embodiments, in vivo scintigraphymay include linking a corticosteroid described herein with a detectableradioisotope, formulating the labeled corticosteroid into a compositiondescribed herein, administering the composition to a subject anddetecting and/or measuring the adherence of the pharmaceuticalcomposition or corticosteroid to the surface of the gastrointestinaltract (e.g., the surface of the esophagus) with a device (e.g., camera)that detects and/or measures radioactivity. In certain embodiments, anin vitro assay for detecting adherence of a pharmaceutical compositionor corticosteroid described herein to a surface of the gastrointestinaltract (e.g., the surface of the esophagus) may include applying acomposition described herein to a distal portion of a strip ofgastrointestinal surface tissue (e.g., porcine esophageal tissue) andsubjecting the composition to a flow of artificial saliva in thedirection of the opposite distal portion of the strip. Determination ofadherence of the composition and/or corticosteroid may be determined ata given time by detecting either the amount of composition and/orcorticosteroid eluted or the amount of composition and/or corticosteroidremaining on the gastrointestinal surface tissue.

In some embodiments, a pharmaceutical composition described herein (or acorticosteroid administered in a composition described herein) has anesophageal transit time of more than 5, 10, 15, 30 or 45 seconds or 1,1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or60 minutes, wherein the esophageal transit time is the lag time fromadministration (e.g., orally and/or to the esophagus) of apharmaceutical composition described herein until activity falls to ≦10%of peak activity. In certain embodiments, a pharmaceutical compositiondescribed herein (or a corticosteroid administered in a compositiondescribed herein) has an esophageal mean transit time of about 5, 10,15, 30 or 45 seconds or 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,30, 35, 40, 45, 50, 55 or 60 minutes. In some embodiments, apharmaceutical composition described herein (or a corticosteroidadministered in a composition described herein) has an esophagealemptying of less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% ten seconds afterpeak activity.

Optional viscosity-enhancing excipients used in pharmaceuticalcompositions described herein include, by way of non-limiting example, acrosslinked poly(acrylic acid) (e.g., Carbopol 974P), glycerine, acarbomer homopolymer, a carbomer copolymer, acacia (gum arabic), agar,aluminum magnesium silicate, sodium alginate, sodium stearate,bladderwrack, bentonite, carbomer, carrageenan, Carbopol, cellulose,microcrystalline cellulose (MCC), ceratonia, chondrus, dextrose,furcellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose, sucrose,maltodextrin, mannitol, sorbitol, honey, maize starch, wheat starch,rice starch, potato starch, gelatin, sterculia gum, xanthum gum,polyethylene glycol (e.g. PEG 200-4500) gum tragacanth, ethyl cellulose,ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose,hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,polygeline, povidone, propylene carbonate, methyl vinyl ether/maleicanhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate),poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose,hydroxypropylmethyl-cellulose, carboxymethyl-cellulose (CMC) (including,e.g., sodium carboxymethyl-cellulose (NaCMC)), silicon dioxide,polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrinand sucralose) or combinations thereof.

In certain embodiments, a pharmaceutical composition described herein isa non-newtonian fluid or a newtonian fluid. In some embodiments, apharmaceutical composition described herein is a non-newtonian fluid. Inspecific embodiments, the non-newtonian fluid is a plastic,pseudo-plastic or dilatant non-newtonian fluid. In some specificembodiments, the non-newtonian fluid is thixotropic. In certainembodiments, the non-newtonian fluid composition thins with shear, andthickens upon the absence of shear. Thus, in some embodiments, providedherein is a fluid pharmaceutical composition that is suitable for easypouring following mild or moderate agitation. Furthermore, in someembodiments, provided herein is a fluid pharmaceutical composition thatwhile being suitable for easy pouring following mild or moderateagitation becomes viscous enough upon oral administration to allow thepharmaceutical composition to at least partially coat the esophagus andtopically deliver a therapeutically effective amount of corticosteroidto the esophagus.

In certain embodiments, the pharmaceutical compositions provided hereinare used to treat, prevent or alleviate inflammatory diseases involvingthe gastrointestinal tract, including the esophagus, stomach and/ordigestive tract. In some embodiments, the pharmaceutical composition isin liquid form. Liquid forms include, by way of non-limiting example,emulsions, solutions, suspensions, syrups, slurries, dispersions,colloids and the like. Also provided are pharmaceutical compositionscomprising a corticosteroid (e.g., a topical corticosteroid, such as,for example, budesonide) and a mucoadhesive agent in the form of adissolving tablet, a dissolving wafer, a capsule, or a gel capsule. Insome embodiments, a pharmaceutical composition described herein is inliquid, semi-solid or solid form. In specific embodiments, apharmaceutical composition described herein is in semi-solid form, e.g.,a gel, a gel matrix, a cream, a paste, or the like. In some embodiments,semi-solid forms comprise a liquid vehicle.

The methods and compositions of the present invention are used byindividuals of any age. By “individual” is meant any animal, forexample, a mammal, or, for example, a human, including, for example,patients in need of treatment.

By “individual” is meant any animal, for example, a mammal, or, forexample, a human, including, for example, patients in need of treatment.In some embodiments, the human is a child. Children are often in need oftreatment because they tend to have the most difficulty using the puffand swallow technique. In certain embodiments, the methods of thepresent invention are used for individuals of any age, including adults.

In certain embodiments, the compositions provided herein are preparedutilizing any suitable source of active agents. In some embodiments,corticosteroid (e.g., budesonide) used in the compositions describedherein are neat corticosteroid (e.g., budesonide). In some embodiments,the neat corticosteroid (e.g., budesonide) is neat, bulk corticosteroid.In certain embodiments, the neat corticosteroid (e.g., budesonide) ispowder corticosteroid (e.g., budesonide). In specific embodiments, theneat corticosteroid (e.g., budesonide) is micronized corticosteroid(e.g., budesonide).

In some embodiments, the corticosteroid is administered in acommercially available formulation. In other embodiments, thecorticosteroid is administered in a composition comprising acommercially available formulation of a corticosteroid. For example, insome embodiments, the corticosteroid containing composition comprises acommercially available formulation and an excipient, such as anexcipient that imparts a mucoadhesive characteristic to the compositionand/or a diluent. In some embodiments, wherein the corticosteroid isbudesonide, the commercially available formulation is PulmicortRespules®. In other embodiments, wherein the corticosteroid isbudesonide, the commercially available formulation is Rhinocort Aqua®.In some embodiments, wherein the corticosteroid is fluticasone, thecommercially available formulation is Flonase®. In some embodiments, theratio of commercially available formulation to the optional diluent isbetween about 1:0.5 and about 1:100. Diluents include anypharmaceutically acceptable oral diluent including, e.g., powderdiluents (such as talc) and liquid diluents (such as water, ethanol andcombinations thereof). In certain embodiments, the commerciallyavailable formulation is Entocort®. In certain embodiments, Entocort®formulations are dissolved and/or dispersed in an aqueous vehicle. Inspecific embodiments, the Entocort® formulation is dispersed in a liquidvehicle that has a pH sufficient to remove the enteric coating from thebudesonide particles. In other embodiments, the Entocort® formulation ispre-treated with a solvent having a pH sufficient to remove the entericcoating from the budesonide particles therein, and the particles aresubsequently formulated into a composition described herein.

In certain embodiments, the corticosteroid containing compositioncomprises micronized budesonide, disodium edetate, sodium chloride,sodium citrate, citric acid, polysorbate (e.g., polysorbate 80), water,and optionally one or more excipients, wherein the excipients areselected from any of those recited herein. In certain embodiments, thecomposition comprises about 0.1 mg to about 1.0 mg budesonide/2 mL (orabout 0.05 mg to about 0.5 mg per gram) of composition. In someembodiments, the composition comprises about 0.2 mg to about 0.6 mgbudesonide/2 mL (or about 0.1 mg to about 0.3 mg per gram) ofcomposition. In specific embodiments, the composition comprises about0.25 mg/2 mL composition. In other specific embodiments, the compositioncomprises about 0.5 mg/2 mL composition.

In other embodiments, the corticosteroid containing compositioncomprises micronized budesonide, microcrystalline cellulose (MCC),carboxymethyl cellulose (including, e.g., carboxymethyl cellulosesodium), dextrose, polysorbate (e.g., polysorbate 80), disodium edetate,potassium sorbate, water, optionally hydrochloric acid and optionallyone or more excipients, wherein the excipients are selected from any ofthose recited herein. In specific embodiments, the composition has a pHof about 4.5. In some embodiments, the composition comprises about 0.1mg to about 1.0 mg of budesonide/g of composition. In certainembodiments, the composition comprises about 0.3 mg to about 0.6 mg ofbudesonide/g of composition. In specific embodiments, the compositioncomprises about 0.4 mg or 0.44 mg of budesonide/g of composition. Incertain specific embodiments, the composition comprises about 3.8 mg/8.6g composition. In some embodiments, the composition comprises about 0.1mg to about 1.0 mg of budesonide/mL of composition (about 0.01 to about0.1% w/w). In certain embodiments, the composition comprises about 0.3mg to about 0.8 mg of budesonide/nm of composition (about 0.03 to about0.08% w/w). In specific embodiments, the composition comprises about 0.6to about 0.7 mg of budesonide/mL of composition (about 0.06 to about0.07% w/w). In more specific embodiments, the composition comprisesabout 0.63 mg of budesonide/mL of composition (about 0.063% w/w).

In some embodiments, the corticosteroid containing composition comprisesmicrofine fluticasone propionate, microcrystalline cellulose,carboxymethyl cellulose (including, e.g., carboxymethyl cellulosesodium), dextrose, benzalkonium chloride, polysorbate (e.g., polysorbate80), phenylethylalcohol, and optionally one or more excipients, whereinthe excipients are selected from those recited herein. In someembodiments, the composition has a pH of between about 5 and about 7. Incertain embodiments, the composition comprises about 20 to about 80 μgfluticasone propionate/mg composition. In some embodiments, thecomposition comprises about 40 to about 60 μg fluticasone propionate/mgcomposition. In specific embodiments, the composition comprises about 50μg fluticasone propionate/mg composition. In some embodiments, thecomposition comprises about 0.02% w/w benzalkonium sodium and about0.25% w/w phenylethyl alcohol.

Formulations

While the compositions of the present invention will typically be usedin therapy for human patients, in certain embodiments, they are used inveterinary medicine to treat similar or identical diseases. In someembodiments, the compositions are used, for example, to treat mammals,including, but not limited to, primates and domesticated mammals. Insome embodiments, the compositions are used, for example, to treatherbivores. The compositions of the present invention include geometricand optical isomers.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredient or ingredients arecontained in an effective amount to achieve its intended purpose.

The exact dosage will depend upon the route of administration, the formin which the composition is adminstered, the subject to be treated, theage, body weight/height of the subject to be treated, and the preferenceand experience of the attending physician. In certain embodiments, theoptimal concentration of the corticosteroid in the composition dependsupon the specific corticosteroid used, the characteristics of thepatient, and the nature of the inflammation for which the treatment issought. In various embodiments, these factors are determined by those ofskill in the medical and pharmaceutical arts in view of the presentdisclosure.

Generally, a therapeutically effective dose is desired. Atherapeutically effective dose refers to the amount of thecorticosteroid that results in a degree of amelioration of symptomsand/or inflammation relative to the status of such symptoms and/orinflammation prior to treatment. The dosage forms and methods ofapplying dosage forms containing effective amounts are within the scopeof the instant invention. In various embodiments, the amount ofcorticosteroid (e.g., budesonide or fluticasone propionate) used in amethod or in a composition described herein is from about 2.5 to 400μg/kg of body weight per day, or for example, in the range of 5 to 300μg/kg per day, or for example in the range of 5 to 200 μg/kg per day, orfor example in the range of 5 to 100 μg/kg per day, or for example inthe range of 10 to 100 μg/kg per day, or for example in the range of10-50 μg/kg per day, or for example in the range of 10-100 μg/kg/day, orfor example in the range of 5-50 μg/kg/day, or in an illustrativeembodiment in the range of 10-60 μg/kg/day. In some embodiments, theamount of corticosteroid (e.g., budesonide or fluticasone propionate)used in a method, in a combination or a dose of a combination disclosedherein includes, by way of non-limiting example, about 50 μg to about500 mg, about 50 μg to about 200 mg, about 50 μg to about 100 mg, about50 μg to about 50 mg, about 100 μg to about 20 mg, about 250 μg to about20 mg, about 250 μg to about 15 mg, about 250 μg to about 10 mg, about250 μg to about 5 mg, about 300 μg to about 4 mg, about 350 μg to about2 mg about 250 μg to about 3 mg, or about 500 μg to about 3 mg, about375 μg to about 1.5 mg, or about 500 μg to about 2 mg, or about 1 mg toabout 3 mg. In an illustrative embodiment, the dosage is provided in asufficient volume to allow the composition to reach the esophagus in aneffective amount. In some embodiments, a composition described hereincomprises 1 or more doses. In certain embodiments, a compositiondescribed herein is contained in a multiple unit container. Thus,provided herein is a kit comprising a composition described herein and acontainer (e.g., a multiple unit or single unit container). In certainembodiments, provided herein is a composition or a kit comprising acomposition that comprises from about 2 and about 180, about 10 to about60, about 14 or about 30 doses.

In an illustrative embodiment a dosage or amount (including a divideddose) of corticosteroid is provided in a composition of sufficientvolume to allow any of the compositions disclosed herein to reach thetargeted and/or inflamed portion of the gastrointestinal tract,including, e.g., the esophagus, in an effective amount. In someembodiments, the effective amount of the composition delivered to theesophagus is an amount sufficient to coat or at least partially coat theesophagus, and deliver the composition to the affected areas, includingby way of example only, the lower esophagus, the esophageal-stomachjuncture, the stomach and/or the duodenum. In certain embodiments, acomposition described herein has a volume of, for example about 1-50 mL,or for example about 1-40 mL, or for example about 1-30 mL, or forexample about 1-25 mL, or for example about 1-20 mL, or for exampleabout 5-25 mL, or for example about 10-20 mL, or for example about 10mL, or for example, about 15 mL, or for example, about 20 mL, or forexample about 1-15 mL, or for example about 1-10 mL, or for exampleabout 2-8 mL, or for example about 3-7 mL, or for example, about 4-6 mL,or for example, about 5 mL, or for example about 6-14 mL, or for exampleabout 8-12 n×L, or for example, about 9-11 mL, or for example, about 10mL. In more specific embodiments, about 0.25 mg to about 6 mg, about0.375 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about1.5 mg, or about 2 mg of corticosteroid (e.g., budesonide) is formulatedinto a single or unit dose of a pharmaceutical composition describedherein, the single or unit dose having a total volume of about 10-20 mL,or for example about 10 mL, or for example, about 15 mL, or for example,about 20 mL, or for example about 1-15 mL, or for example about 1-10 mL,or for example about 2-8 mL, or for example about 3-7 mL, or forexample, about 4-6 mL, or for example, about 5 mL, or for example about6-14 mL, or for example about 8-12 mL, or for example, about 9-11 mL, orfor example, about 10 mL. As discussed herein, “liquid” encompassesslurries, solutions, suspensions, dispersions or any combinationthereof, depending on the solubilities and amounts of the individualcomponents and the vehicles and solvents used. In some embodiments, anappropriate palatable dosage is in a volume sufficient to coat or atleast partially coat the esophagus, and in an illustrative embodiment,the volume is sufficient to coat or at least partially coat theesophagus and deliver the corticosteroid to the affected areas,including by way of example only, the lower esophagus, theesophageal-stomach juncture, the stomach and/or the duodenum. Thecomposition may be delivered, for example, four times a day, three timesa day, twice a day, once a day, every other day, three times a week,twice a week, or once a week. The dosage may, for example, be dividedinto multiple doses throughout the day, or be provided, for example, infour, three, two, or one dose a day. In certain instances,administration more frequent administration (e.g., b.i.d. versus once aday) provides for a shorter overall therapy or a quicker onset ofsymptom resolution. In one illustrative example, the dose is providedonce a day.

In certain embodiments, a dose or composition described herein isadministered with food. In some embodiments, a dose or compositiondescribed herein is administered without food. In certain embodiments, adose or composition described herein is administered in a fed or fastedstate. In some embodiments, a dose or composition described herein isadministered in the morning, in the afternoon, in the evening, at night,or a combination thereof. In some embodiments, the dose is administeredat night. In another aspect, the dose is administered about 30 minutesprior to bed, with no food or water given after administration of thecompositions herein. In yet another embodiment of the instant invention,the dose is administered prior to bedtime, wherein after administrationof the composition, the patient or individual is in a substantiallysupine position for at least 30 minutes, at least 1 hour, at least 2hours, at least 4 hours or at least 8 hours.

In some embodiments, provided herein are methods of treating,preventing, or alleviating inflammation or symptoms associated withinflammation of the gastrointestinal tract, e.g., the esophagus,comprising administering to an individual in need thereof a single unitdose of a pharmaceutical composition described herein from a multidosecontainer. In specific embodiments, administering a single unit dosefrom a multi dose container comprises (1) shaking a multidose container,the multidose container comprising at least one unit dose of apharmaceutical composition described herein; (2) pouring (or otherwisedispensing) a single unit dose from the multidose container into anadministration device (e.g., a device suitable for administering to ahuman individual, such as a spoon, cup or syringe); and (3)administering the single unit dose to the individual in need thereof. Inmore specific embodiments, shaking of the multidose container occursuntil the fluid therein has a viscosity suitable for pouring (e.g., easypouring). In some specific embodiments, the process further compriseswaiting after pouring the single unit dose and prior to administeringthe single unit dose to the individual in need thereof. In specificembodiments, the wait time is a time sufficient to allow the viscosityof composition to achieve a desired level, e.g., a viscosity to improvethe coating capabilities of the composition. In some embodiments, thewait time is, e.g., about 3 seconds, or more; about 5 seconds, or more;about 10 seconds, or more; about 15 seconds, or more; about 20 seconds,or more; about 25 seconds, or more; about 30 seconds, or more; about 40seconds, or more; about 45 seconds, or more; about 50 seconds, or more;or about 60 seconds, or more. In other specific embodiments, thecomposition is administered immediately following pouring thecomposition into the administration device. In some embodiments, theprocess comprises shaking the multidose container well.

In some embodiments, initial treatment continues, for example, for about3 days to 2 weeks for an acute condition, or about 4 weeks to about 16weeks for a chronic condition, or about 8 weeks to about 12 weeks for achronic condition. In various embodiments, longer therapy is needed,such as, for example, therapy similar to chronic therapy for persistentasthma. In some aspects of the present invention, patients are, forexample, be treated for up to 6 months, or up to one year. In certainaspects, maintenance treatments last up to or longer than one year. Insome embodiments, patients are treated on a maintenance basis or on anas needed basis during a problematic episode, depending on the severityof the condition. In certain embodiments, patients are treated on arotating treatment basis, where treatment is provided for a period oftime and then the patient is taken off of the drug for a period beforetreatment resumes again. When off the drug, the patient may be given notreatment, treatment with another medication, or treatment with areduced dosage. In certain embodiments, patients are given treatmentwith a higher dose of the composition until a desired reduced diseasestate is achieved, and then continued on a lower dose of thecomposition.

In some embodiments, the corticosteroid is present in a pharmaceuticalcomposition described herein in any effective amount. In someembodiments, an effective amount is an amount sufficient to reduceinflammation or symptoms of inflammation associated with an inflammatorydisease or condition of the gastrointestinal tract (e.g., the esophagus)as compared to the level of inflammation or symptoms of inflammationassociated with an inflammatory disease prior to administration of theeffective amount. In certain embodiments, effective amount is an amountsufficient to maintain a reduction in inflammation or symptoms ofinflammation achieved in any manner including, but not limited to, bythe administration of an effective amount sufficient to achieve such areduction. In some embodiments, the effective amount is about 0.05 mg toabout 10 mg, about 0.05 mg to about 7.5 mg, about 0.05 mg to about 5 mg,about 0.25 mg to about 3 mg, about 0.25 mg to about 2.5 mg, about 0.5 mgto about 3 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 0.1 mg,about 0.5 mg to about 5 mg, about 0.5 mg to about 4 mg, about 1 mg toabout 4 mg, about 1 mg to about 3 mg, about 2 mg to about 3 mg, or about2 mg to about 4 mg. In specific embodiments, the effective amount ofcorticosteroid is about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.25mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.37 mg, about0.375 mg, about 0.7 mg, about 0.8 mg, about 0.75 mg, about 1 mg, about1.2 mg, about 1.25 mg, about 1.3 mg, about 1.5 mg, about 2 mg, about 2.5mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg,about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, or about 7.5 mg ormore. In certain embodiments, the corticosteroid is present in apharmaceutical composition at a concentration of about 0.01 mg/mL toabout 2 mg/mL of composition. In specific embodiments, thecorticosteroid is present in a pharmaceutical composition at aconcentration of about 0.01 mg/mL to about 1.5 mg/mL, about 0.03 mg/mLto about 1.5 mg/mL, about 0.05 mg/mL to about 1.5 mg/mL, or about 0.07mg/mL to about 1.5 mg/mL. In more specific embodiments, thecorticosteroid is present in a pharmaceutical composition at aconcentration of about 0.07 mg/mL to about 1 mg/mL.

In specific embodiments, the composition described herein is ancomposition comprising a corticosteroid, dextrose, maltodextrin,edetate, citrate, polysorbate 80, an optional preservative, an optionalflavoring agent, an optional sweetener, at least one additionalexcipient, and a liquid vehicle. In specific embodiments, thecomposition comprises a preservative. In further or alternativeembodiments, the composition comprises a flavoring agent. In further oralternative embodiments, the liquid vehicle is an aqueous medium (e.g.,water). In specific embodiments, corticosteroid particles (e.g.,microparticles) are suspended in the aqueous medium.

In some embodiments, the corticosteroid is selected from, by way ofnon-limiting example, budesonide, fluticasone propionate andcombinations thereof. In specific embodiments, corticosteroid (e.g.,budesonide or fluticasone propionate) is present in a composition orformulation described herein in an amount of about 0.005 mg/mL to about1.5 mg/mL, or about 0.01 mg/mL to about 1 mg/mL, about 0.01 mg/mL toabout 5 mg/mL, about 0.01 mg/mL to about 3 mg/mL, about 0.01 mg/mL toabout 2 mg/mL, about 0.01 mg/mL to about 1.5 mg/mL, about 0.05 mg/mL toabout 0.5 mg/mL, about 0.05 mg/mL to about 0.4 mg/mL, about 0.07 mg/mLto about 1.5 mg/mL, or about 0.07 mg/mL to about 1 mg/mL. In morespecific embodiments, budesonide is present in an amount of about 0.01mg/mL to about 3 mg/mL, about 0.01 mg/mL to about 1.5 mg/mL, about 0.05mg/mL to about 0.5 mg/mL, about 0.05 mg/mL to about 0.4 mg/mL, or about0.07 mg/mL to about 1 mg/mL. In other specific embodiments, fluticasonepropionate is present in an amount of about 0.005 mg/mL to about 1.5mg/mL, or about 0.01 mg/mL to about 1 mg/mL.

In some embodiments, the volume of a composition or dose of acomposition described herein is an amount sufficient to substantiallycoat (e.g., at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, at least 98% or at least 99% of) the length ofthe esophagus of an individual to whom the composition is administered.In certain embodiments, the volume of a composition or a dose of acomposition described herein is about 0.05 mL/cm esophageal length toabout 1 mL/cm esophageal length, about 0.1 mL/cm esophageal length toabout 0.8 mL/cm esophageal length, about 0.2 mL/cm esophageal length toabout 0.6 mL/cm esophageal length, or about 0.3 nm/cm esophageal lengthto about 0.5 mL/cm esophageal length, wherein the esophageal length isthe esophageal length of the individual to whom the composition isadministered. In some embodiments, the volume of a composition or doseof a composition described herein is based on the esophageal length ofan individual (e.g., male, female, or both) that is in the 50^(th)percentile of height for their age. Therefore, in some embodiments, thevolume of a composition or dose of a composition described herein isabout 0.05 mL/cm esophageal length to about 1 mL/cm esophageal length,about 0.1 mL/cm esophageal length to about 0.8 mL/cm esophageal length,about 0.2 mL/cm esophageal length to about 0.6 mL/cm esophageal length,about 0.3 mL/cm esophageal length to about 0.5 mL/cm esophageal length,about 0.32 mL/cm esophageal length to about 0.41 mL/cm esophageallength, or about 0.3 mL/cm esophageal length to about 0.46 mL/cmesophageal length, wherein the esophageal length is the esophageallength of an individual having a height in the 50^(th) percentile forthe age of the individual to whom the composition is administered. Incertain instances, esophageal length is the actual esophageal length ofthe individual or is calculated based on the equation: esophageallength=1.048 (cm)+(0.167*height (cm)). In certain instances, forexample, the 50^(th) percentile height (CDC 2000) for male children age2 is 87 cm, age 3 is 95 cm, age 4 is 102 cmn, age 5 is 109 cm, age 6 is115 cm, age 7 is 122 cm, age 8 is 128 cm, age 9 is 134 cm, age 10 is 139cm, age 11 is 144 cm, age 12 is 149 cm, age 13 is 156 cm age 14 is 164cm, age 15 is 170 cm, age 16 is 174 cm, age 17 is 175 cm, and age 18 is176 cm.

Furthermore, in certain embodiments, the amount of a therapeutic agent(e.g., a corticosteroid such as budesonide) in a composition or a doseof a composition described herein is about 0.005 mg/cm esophageal lengthto about 0.3 mg/cm esophageal length, about 0.008 mg/cm esophageallength to about 0.2 mg/cm esophageal length, about 0.01 mg/cm esophageallength to about 0.15 mg/cm esophageal length, or about 0.015 mg/cmesophageal length to about 0.1 mg/cm esophageal length, wherein theesophageal length is the esophageal length of the individual to whom thecomposition is administered. In some embodiments, the volume of acomposition or dose of a composition described herein is based on theesophageal length of an individual (e.g., male, female, or both) that isin the 50^(th) percentile of height for their age. Therefore, in someembodiments, the amount of a therapeutic agent (e.g., a corticosteroidsuch as budesonide) in a composition or dose of a composition describedherein is about 0.005 mg/cm esophageal length to about 0.3 mg/cmesophageal length, about 0.008 mg/cm esophageal length to about 0.2mg/cm esophageal length, about 0.01 mg/cm esophageal length to about0.15 mg/cm esophageal length, or about 0.015 mg/cm esophageal length toabout 0.1 mg/cm esophageal length, wherein the esophageal length is theesophageal length of an individual having a height in the 50^(th)percentile for the age of the individual to whom the composition isadministered.

In some embodiments, any pharmaceutical composition or dose of apharmaceutical composition described herein is provided or administeredin a volume sufficient to provide a bolus when orally administered to anindividual. In certain embodiments, the composition has a volume thatdoes not systemically deliver excessive amounts of the active agent. Insome embodiments, the pharmaceutical composition or dose is provided ina volume sufficient to provide a bolus when administered to anindividual, wherein the size of the bolus at the distal end of theesophagus (e.g., the size of the bolus prior, e.g., immediately prior,to entering or passing the lower esophageal sphincter) is less than 90%,less than 85%, less than 80%, less than 75%, less than 70%, less than65%, less than 60%, less than 55%, less than 50%, less than 45%, lessthan 40%, less than 35%, less than 30%, less than 25%, less than 20%,less than 15%, less than 10% or less than 5% of size of the bolus thatentered the esophagus (e.g., the size of the bolus after, e.g.,immediately after, passing the upper esophageal sphincter). In someembodiments, the size of the bolus is determined as a measure ofdiameter or of volume. In certain embodiments, diameter of the sphinctercan be determined using gamma scintigraphy techniques. In specificembodiments, the volume of the composition or dose is adjusted given thelength and/or diameter of the esophagus of the individual to whom thecomposition or dose is administered.

In other illustrative embodiments of the invention, the compositionsdisclosed herein are provided in the form of a lozenge which may bedissolved in the mouth, thus reaching and at least partially coating theesophagus, and deliver the composition to the affected areas, includingby way of example only, the lower esophagus, the esophageal-stomachjuncture, the stomach and/or the duodenum. The lozenge or other similardosage form (e.g., a tablet, capsule, or other solid), would dissolve inthe mouth or esophagus to produce a solution that can then at leastpartially coat the esophagus, and thereafter deliver the composition tothe affected areas, including by way of example only, the loweresophagus, the esophageal-stomach juncture, the stomach and/or theduodenum. Or, for children, infants or other patients that may havedifficulty with a dissolving lozenge, the lozenge may be ground orotherwise dissolved in a small volume of water or other pharmaceuticallysuitable liquid, for example, reaching a total volume presented inembodiments herein. In other illustrative embodiments of the invention,the compositions disclosed herein are provided in the form of a tablet,a capsule, or, for example a gel capsule, designed for slow release anddelivery to the gastrointestinal tract, including the esophagus.

In some embodiments, initial treatment continues, for example, for about3 days to 2 weeks for an acute condition, or about 4 weeks to about 16weeks for a chronic condition, or about 8 weeks to about 12 weeks for achronic condition. In various embodiments, longer therapy is needed,such as, for example, therapy similar to chronic therapy for persistentasthma. In some aspects of the present invention, patients are, forexample, be treated for up to 6 months, or up to one year. In certainaspects, maintenance treatment last up to or longer than one year. Insome embodiments, patients are treated on a maintenance basis or on anas needed basis during a problematic episode, depending on the severityof the condition. In certain embodiments, patients are treated on arotating treatment basis, where treatment is provided for a period oftime and then the patient is taken off of the drug for a period beforetreatment resumes again. When off the drug, the patient may be given notreatment, treatment with another medication, dietary therapy, ortreatment with a reduced dosage. In certain embodiments, patients aregiven treatment with a higher dose of the composition until a desiredreduced disease state is achieved, and then continued on a lower dose ofthe composition. In certain embodiments, a patient combines treatmentwith a composition described herein with a treatment with anothermedication, and/or dietary therapy. In certain embodiments, patients aregiven treatment with a higher dose of the composition until a desiredreduced disease state is achieved, and then continued on a lower dose ofthe composition.

In some embodiments, methods of treatment described herein includeintermittent or continuous treatments. In certain embodiments, a methodof treating gastrointestinal inflammation described herein includesprophylactic treatment of gastrointestinal inflammation (e.g., atreatment that prevents symptoms and/or inflammation from occurring). Insome embodiments, a method of treating gastrointestinal inflammationdescribed herein includes a method of prolonging and/or maintainingremission of gastrointestinal inflammation by administering orcontinuing to administer a pharmaceutical composition as describedherein after inflammation and/or symptoms of inflammation are inremission. In specific embodiments, prophylactic and/or remissivetherapies optionally comprise administration of a composition describedherein comprising a reduced amount of corticosteroid compared to theamount of corticosteroid utilized when the inflammation and/or symptomsof inflammation are not in remission.

In some embodiments, provided herein is a method of diagnosing anindividual with gastrointestinal inflammation (e.g., EoE) byadministering a pharmaceutical composition described herein; anddetermining the efficacy of such a treatment. In certain instances, theindividual is a patient who has gastrointestinal inflammation and/orsymptoms thereof that are refractory to at least one acid inhibitor(e.g., PPI and/or H2A). In some embodiments, effective treatment of thegastrointestinal inflammation with a composition described herein is apositive indication of EoE. In certain embodiments, this method ofdiagnosis is used instead of an esophageal biopsy.

In various embodiments, the compositions of the present inventioninclude pharmaceutically acceptable salts. Pharmaceutically acceptablesalts are generally well known to those of ordinary skill in the art andinclude, by way of non-limiting example, acetate, benzenesulfonate,besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate,carnsylate, carbonate, citrate, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate,maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate(embonate), pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,or teoclate. Other pharmaceutically acceptable salts may be found in,for example, Remington: The Science and Practice of Pharmacy (20.sup.thed.) Lippincott, Williams & Wilkins (2000). In specific embodiments,pharmaceutically acceptable salts include, for example, acetate,benzoate, bromide, carbonate, citrate, gluconate, hydrobromide,hydrochloride, maleate, mesylate, napsylate, pamoate (embonate),phosphate, salicylate, succinate, sulfate, or tartrate. In certainembodiments, such salts are used for any of the corticosteroidsdescribed herein.

Depending on the specific conditions being treated, the compositions maybe formulated into liquid or solid dosage forms and administeredsystemically or locally. In some embodiments, the agents are delivered,for example, in a timed- or sustained-low release form as is known tothose skilled in the art. Techniques for formulation and administrationmay be found in Remnington: The Science and Practice of Pharmacy (20thed.) Lippincott, Williams & Wilkins (2000).

In addition to the active or actives, various embodiments of the presentinvention provide for pharmaceutical compositions that contain suitablepharmaceutically acceptable excipients and auxiliaries. For example, insome embodiments, pharmaceutically acceptable excipients and/orauxiliaries are used to formulate the corticosteroids herein disclosedfor the practice of the invention into dosages suitable for systemicadministration is within the scope of the invention. In someembodiments, the corticosteroid is formulated readily usingpharmaceutically acceptable excipients and/or auxiliaries well known inthe art into dosages suitable for oral administration. Such excipientsand/or auxiliaries enable the compositions of the invention to beformulated as tablets, pills, dragees, capsules, liquids, soft chews,creams, pastes, chewable tablets, gels or gel matrices, syrups,slurries, suspensions, gums, lozenges, and the like, for oral ingestionby a patient to be treated. In certain instances, oral formulations(e.g., suspensions, creams or gel matrices) are formulated such thatupon oral administration, an interface layer between the oralformulation (e.g., suspension, cream or gel matrix) and a surface of thegastrointestinal tract (e.g., the surface of the esophagus) is formed.In some instances, an oral formulation (e.g., suspensions, creams or gelmatrices) in contact with a surface of the gastrointestinal tract (e.g.,the surface of the esophagus) delivers a corticosteroid onto and/orthrough the surface of the gastrointestinal tract (e.g., the surface ofthe esophagus) via the interface layer and as the oral formulations(e.g., suspensions, creams or gel matrices) near the interface layer isdepleted of corticosteroid, a concentration gradient results. In certaininstances, portions of the oral formulations (e.g., suspensions, creamsor gel matrices) with high concentrations of corticosteroid relative tothe portions of the oral formulations (e.g., suspensions, creams or gelmatrices) proximate to the interface layer replenishes corticosteroid inthe portion of the oral formulations (e.g., suspensions, creams or gelmatrices) proximate to the interface layer. In certain instances, uponoral administration of an oral formulation described herein to anindividual, an interface layer is formed between a surface of thegastrointestinal tract (e.g., the surface of the esophagus) and amixture of the oral formulation (e.g., chewable tablet) and saliva ofthe individual.

In certain embodiments, pharmaceutical preparations for oral use areobtained by combining the corticosteroids with solid excipients,optionally grinding a resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include, by way ofnon-limiting example, fillers such as sugars or starches, includingdextrose, lactose, maltodextrin, sucrose, sucralose, mannitol, orsorbitol; cellulose preparations, for example, maize starch, wheatstarch, rice starch, potato starch, or a combination thereof.Disintegrating agents are optionally added, such as the cross-linkedpolyvinylpyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate. In some embodiments, the pharmaceutical compositionsused herein include excipients suitable for rendering the dissolvingtablet palatable, such as sweeteners or flavoring agents.

In some embodiments, the pharmaceutical compositions described hereinare in liquid form. Appropriate excipients for use in liquid formpharmaceutical compositions include, for example, those that increasethe mucoadhesive character of the liquid composition. Optionalexcipients also include, by way of non-limiting example, those thatrender the liquid composition palatable or increase the viscosity of theliquid composition. Optional excipients that increase palatabilityinclude, by way of non-limiting example, sugars, including dextrose,lactose, sucrose, sucralose, maltodextrin, mannitol, or sorbitol; honey,combinations thereof, or the like.

Any of the compositions or formulations described herein optionallycomprise one or more viscosity enhancing agent, optionally comprise oneor more binder, optionally comprise one or more filler, optionallycomprise one or more lubricant, optionally comprise one or more solvent,optionally comprise one or more suspension agent, optionally compriseone or more flavoring agent, optionally comprise one or more coloringagent, optionally comprise one or more sweetener, optionally compriseone or more preservative, optionally comprise one or more antioxidant,optionally comprise one or more buffering agent, optionally comprise oneor more humectant, optionally comprise one or more chelating agent,optionally comprise one or more surfactant, or combinations thereof.

Preservatives include, by way of non-limiting example, benzalkoniumchloride, cetrimide (cetyltrimethylammonium bromide), benzoic acid,benzyl alcohol, methyl-, ethyl-, propyl- and butyl-esters ofpara-hydroxybenzoic acid, chlorhexidine, chlorobutanol, phenylmercuricacetate, borate and nitrate, potassium sorbate, sodium benzoate, sorbicacid, thiomersal (mercurithiosalicylate), combinations thereof, or thelike. Compositions and formulations described herein optionally includeabout 0.1% w/w to about 5% w/w, about 0.1% w/w to about 3% w/w, about0.1% w/w to about 1% w/w, about 0.1% w/w to about 0.5% w/w, about 0.2%w/w of one or more preservative(s).

Antioxidants include, by way of non-limiting example, ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate,sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or aderivative thereof, propyl gallate, edetate (EDTA) (e.g., disodiumedetate), Diethylenetriaminepentaacetic acid (DTPA), Triglycollamate(NT), combinations thereof, or the like. Compositions and formulationsdescribed herein optionally include of about 0.01% w/w to about 1% w/w,about 0.01% w/w to about 0.5% w/w, about 0.01% w/w to about 0.3% w/w, orabout 0.01% w/w to about 0.1% w/w one or more antioxidants).

Buffering agents include, by way of non-limiting example, citratebuffers (i.e., citric acid and citrate), phosphate buffers, acetatebuffers, combinations thereof, or the like.

As used herein, “citrate” includes all compounds of Formula I whereineach R is independently selected from an H and a negative charge (e.g.,as a salt or as a disassociated salt or acid). In certain embodiments,citrate is selected from, by way of non-limiting example, sodiumcitrate, citric acid and the like.

Humectants include, by way of non-limiting example, glycerine, propyleneglycol, ethylene glycol, glyceryl triacetate, polyols (e.g., sorbitol,xylitol, maltitol, polydextrose), and the like. Compositions andformulations described herein optionally include about 0.1% w/w to about10% w/w, about 1% w/w to about 10% w/w, about 1% to about 8% w/w, orabout 5% w/w of a humectant. In certain embodiments, humectants inhibitprecipitation and/or crystallization of one or more component of acomposition or formulation described herein (e.g., a sweetener,mucoadhesive agent or a viscosity enhancing agent).

Chelating agents include, by way of non-limiting example, edetate (EDTA)(e.g., disodium edetate), Diethylenetriaminepentaacetic acid (DTPA),Triglycollamate (NT), or the like. Compositions and formulationsdescribed herein optionally include about 0.01% w/w to about 0.5% w/w,about 0.01% w/w to about 0.3% w/w, or about 0.01% w/w to about 0.1% w/w,or about 0.05% w/w of one or more chelating agent.

As used herein, “edetate” includes all compounds of Formula II whereineach R is independently selected from an H and a negative charge (e.g.,as a salt or as a disassociated salt or acid). In certain embodiments,edetate is selected from, by way of non-limiting example, disodiumedetate, calcium edetate, ethylenediaminetetraacetic acid and the like.

In certain embodiments, sweeteners include, by way of non-limitingexample, glycerin, acesulfame potassium (AceK), mono-ammoniumglycyrrhizinate (e.g., Magnasweet®), sucrose, lactose, glucose,fructose, arabinose, xylose, ribose, mannose, galactose, dextrose,sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol and the like.In some embodiments, flavoring agents include, by way of non-limitingexample, peppermint, orange, bubble gum, wintergreen, grape and cherry.

Surfactants include, e.g., anionic, cationic, non-ionic, or zwitterionicsurfactants, such as, by way of non-limiting example, polysorbate (e.g.,polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80,polysorbate 81, polysorbate 85, polysorbate 120), bile acids or theirsalts (e.g., sodium taurocholates, sodium deoxytaurocholates,chenodeoxycholic acid, and ursodeoxycholic acid), nonoxynol orpolyoxyethylene glycol fatty acid esters, pluronic or poloxamers such asPluronic F68, Pluronic L44, Pluronic L101, combinations thereof, or thelike. Compositions and formulations described herein optionally includeabout 0.001% w/w to about 0.5% w/w, about 0.001% w/w to about 0.3% w/w,or about 0.001% w/w to about 0.1% w/w of one or more surfactant.

Dragee cores are provided with suitable coatings. In some embodiments,concentrated sugar solutions are used for this purpose, which optionallycontain gum arabic, talc, polyvinylpyrrolidone, carbopol gel,polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dye-stuffs orpigments are optionally added to the tablets or dragee coatings foridentification or to characterize different combinations of activecorticosteroid doses.

In various embodiments, pharmaceutical preparations that are used orallyinclude push-fit capsules made of gelatin, as well as soft, sealedcapsules made of gelatin, and a plasticizer, such as glycerol orsorbitol. In some embodiments, the push-fit capsules contain the activeingredient or ingredients in admixture with a filler, binder, lubricant,stabilizer or a combination thereof. Fillers include, by way ofnon-limiting example, lactose. Binders include, by way of non-limitingexample, starches. Lubricants include, by way of non-limiting example,talc and magnesium stearate. In soft capsules, the corticosteroids maybe dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycols (PEGs). In addition,stabilizers are optionally added.

In one embodiment, the present invention provides for a corticosteroidthat has a low bioavailability. Due to the low bioavailability, thecorticosteroid is used in certain embodiments of the invention, thecorticosteroid remains in the gastrointestinal tract, for example, inthe esophagus. In some embodiments, the low bioavailability results indecreased systemic side effects and complications, allowing patientswith chronic conditions to receive treatment for longer periods of time.

In some embodiments, a pharmaceutical composition or dosage formdescribed herein is a suspension or a solution comprising acorticosteroid (e.g., budesonide). In some embodiments, compositions(e.g., suspensions or solutions) comprise a certain concentration ofcorticosteroid (e.g., budesonide) that is dissolved in the liquid medium(e.g., the solvent or liquid vehicle used, such as water, alcohol,aqueous alcohol, or the like). In certain embodiments, the amount ofcorticosteroid (e.g., budesonide) dissolved in the liquid medium (e.g.,in an equilibrated sample) is greater than 4 μg/mL, greater than 5μg/mL, greater than 10 μg/mL, greater than 15 μg/mL, greater than 20μg/mL, greater than 21 μg/mL, greater than 22 μg/mL, greater than 23μg/mL, greater than 24 μg/mL, greater than 25 μg/mL, about 25 μg/mL,greater than 30 μg/mL, about 25 μg/mL to about 80 μg/mL, about 30 μg/mLto about 80 μg/mL, about 30 μg/mL, about 35 μg/mL, about 40 μg/mL, about45 μg/mL, about 50 μg/mL, about 55 μg/mL, about 60 μg/mL, about 65μg/mL, or about 70 μg/mL.

In some embodiments, compositions described herein comprise a certainconcentration of budesonide that is dissolved in the liquid medium(e.g., the solvent or liquid vehicle used, such as water, alcohol,aqueous alcohol, or the like). In specific embodiments, the amount of Repimer of the dissolved budesonide (compared to the overall weight ofthe budesonide) is greater than 28% w/w, greater than 30% w/w, greaterthan 39% w/w, greater than 40%, about 39-50%, about 40-50%, less than38% w/w, about 29%-37% w/w, less than 27% w/w, or the like. In someinstances, the % epimers are obtained in a composition having an overall% R epimer (compared to overall budesonide) of about 50-55% w/w, orabout 53-54% w/w. In certain instances, equilibration of the sample isaccomplished once the concentration of the corticosteroid (e.g.,budesonide) dissolved in the liquid is substantially stable, e.g., after2 days, 3 days, 4 days, 5 days, a week, a month, or the like. Inspecific instances, equilibration of the sample is accomplished after 2days.

In some embodiments, the corticosteroid is administered in acommercially available formulation. In other embodiments, thecorticosteroid is administered in a composition comprising acommercially available formulation of a corticosteroid and formulated asdescribed herein. For example, in some embodiments, the corticosteroidcontaining composition provided herein comprises a commerciallyavailable formulation and an excipient, such as a diluents, a flavoringagent, a mucoadhesive agent a viscosity enhancing agent, a binder, afiller, a lubricant, a solvent, a suspension agent, a coloring agent, asweetener, a preservative, an antioxidant, a buffering agent, ahumectant, a chelating agent, a surfactant, combinations thereof, or thelike. In some embodiments, wherein the corticosteroid is budesonide, thecommercially available formulation is Pulmicort Respules® (distributedby AstraZeneca, e.g., as set forth in NDA 20-929, which is herebyincorporated by reference in its entirety). In other embodiments,wherein the corticosteroid is budesonide, the commercially availableformulation is Rhinocort Aqua® (distributed by AstraZeneca LP,Wilmington, Del. 19850, e.g., as set forth in NDA 20-746, which is,including all supplements, hereby incorporated herein by reference inits entirety). In still other embodiments, wherein the corticosteroid isbudesonide, the commercially available formulation is Symbicort®(manufactured by AstraZeneca Dunkerque Production, Dunkerque, France,e.g., as set forth in NDA 21-929, which is, including all supplements,hereby incorporated herein by reference in its entirety). In someembodiments, wherein the corticosteroid is fluticasone, the commerciallyavailable formulation is Flonase®. In some embodiments, the ratio ofcommercially available formulation to the optional diluent is betweenabout 1:0.5 and about 1:100. Diluents include any pharmaceuticallyacceptable oral diluent including, e.g., powder diluents (such as talc)and liquid diluents (such as water, ethanol and combinations thereof).In certain embodiments, the commercially available formulation isEntocort® (manufactured by AstraZeneca AB, S-151 85 Sodertalje, Sweden,distributed by Prometheus Laboratories Inc, San Diego, Calif. 92121, asset forth in NDA 21-324, which is, including all supplements, herebyincorporated herein by reference in its entirety). In certainembodiments, Entocort® formulations are dissolved and/or dispersed in anaqueous vehicle. In specific embodiments, the Entocort® formulation isdispersed in a liquid vehicle that has a pH sufficient to remove theenteric coating from the budesonide particles. In other embodiments, theEntocort® formulation is pre-treated with a solvent having a pHsufficient to remove the enteric coating from the budesonide particlestherein, and the particles are subsequently formulated into acomposition described herein.

In certain embodiments, a corticosteroid composition described hereincomprises a corticosteroid, a commercially available formulation, and,optionally, one or more additional excipient. In some embodiments, acorticosteroid composition described herein comprises a corticosteroidformulated in a manner similar to a commercial formulation (e.g.,lacking one or more of the active ingredients of the formulation), and,optionally, one or more additional excipient. The one or more additionalexcipients can be utilized to achieve a formulation as described herein.In specific embodiments, the commercially available formulation is UltraXCID (manufactured by Matrixx Initiatives, Inc., Phoenix, Ariz.).

In certain embodiments, a composition provided herein comprises or isprepared by combining the components set forth in any of Tables 1-12. Invarious embodiments, one or more of maltodextrin, dextrose, HEC, CMC,MCC, Carbomer and HPMC are utilized therein.

TABLE 1 Budesonide Composition #1 Ingredient Amount Budesonide 1 mg to150 mg CMC, MCC, Carbomer, HPMC and/or HEC 0.5 g to 10 g Dextrose 0 g to100 g Maltodextrin 0 g to 100 g EDTA (e.g., disodium edetate) 5 mg to200 mg Citric Acid 10 mg to 1 g Citrate (e.g., sodium citrate) 10 mg to2 g Polysorbate 80 (e.g., Tween 80) 5 mg to 100 mg Flavoring Agentoptional Sweetener optional Preservative optional Water q.s. to 100 mL

TABLE 2 Budesonide Composition #2 Ingredient Amount Budesonide 1 mg to150 mg CMC, MCC, Carbomer, HPMC and/or HEC 0 g to 10 g Dextrose 1 g to100 g Maltodextrin 0 g to 100 g EDTA (e.g., disodium edetate) 5 mg to200 mg Citric Acid 10 mg to 1 g Citrate (e.g., sodium citrate) 10 mg to2 g Polysorbate 80 (e.g., Tween 80) 5 mg to 100 mg Flavoring Agentoptional Sweetener optional Preservative optional Water q.s. to 100 mL

TABLE 3 Budesonide Composition #3 Ingredient Amount CMC, MCC, Carbomer,HPMC and/or HEC 0 g to 10 g Dextrose 0 g to 100 g Maltodextrin 1 g to100 g EDTA (e.g., disodium edetate) 5 mg to 200 mg Citric Acid 10 mg to1 g Citrate (e.g., sodium citrate) 10 mg to 2 g Polysorbate 80 (e.g.,Tween 80) 5 mg to 100 mg Flavoring Agent optional Sweetener optionalPreservative optional Water q.s. to 100 mL

TABLE 4 Budesonide Composition #4 Ingredient Amount Budesonide 0.5 mg to2 mg CMC and MCC (e.g., Avicel RC-591) 0.01 g to 0.3 g Dextrose 0.1 g to1 g Maltodextrin 0.5 g to 2 g EDTA (e.g., disodium edetate) 1 mg to 10mg Citric Acid 0.1 mg to 100 mg Citrate (e.g., sodium citrate) 0.1 mg to200 mg Polysorbate 80 (e.g., Tween 80) 0.1 mg to 10 mg Cherry Flavor 1mg to 100 mg Sweetener 100 mg to 1 g Sodium Benzoate 1 mg to 50 mgPotassium Sorbate 1 mg to 50 mg Water q.s. to 5 mL

TABLE 5 Budesonide Composition #5 Ingredient Amount Budesonide 0.5 mg to2 mg CMC and MCC (e.g., Avicel RC-591) 0.02 g to 0.6 g Dextrose 0.2 g to2 g Maltodextrin 1 g to 4 g EDTA (e.g., disodium edetate) 2 mg to 20 mgCitric Acid 0.2 mg to 200 mg Citrate (e.g., sodium citrate) 0.2 mg to400 mg Polysorbate 80 (e.g., Tween 80) 0.2 mg to 20 mg Cherry Flavor 2mg to 200 mg Sweetener 200 mg to 2 g Sodium Benzoate 2 mg to 100 mgPotassium Sorbate 2 mg to 100 mg Water q.s. to 10 mL

TABLE 6 Budesonide Composition #6 Ingredient Amount (mg/mL) Budesonide0.01 to 0.5  CMC and MCC (e.g., Avicel RC-591)   2 to 100 Dextrose   10to 500 Maltodextrin (M150)   10 to 500 EDTA (e.g., disodium edetate)0.01 to 10  Citric acid 0.1 to 10 Citrate (e.g., sodium citrate) 0.1 to10 Polysorbate 80 (e.g., Tween 80) 0.01 to 1  Flavoring agent (e.g.,Cherry Flavor)  0.1 to 100 Glycerin   10 to 100 Acesulfame potassium 0.1to 40 Magnasweet 110 0.1 to 40 Sodium Benzoate 0.1 to 10 PotassiumSorbate 0.1 to 10 Water q.s. to 1-15 mL

TABLE 7 Budesonide Composition #7 Ingredient Amount (mg/mL) Budesonideabout 0.05 to about 0.2 CMC and MCC (e.g., Avicel RC-591)   5 to 50Dextrose   50 to 250 Maltodextrin (M150)   200 to 500 EDTA (e.g.,disodium edetate) 0.1 to 1 Citric acid 0.5 to 5 Citrate (e.g., sodiumcitrate) 0.2 to 2 Polysorbate 80 (e.g., Tween 80)  0.01 to 0.4 Flavoringagent (e.g., Cherry Flavor)   1 to 10 Glycerin   30 to 80 Acesulfamepotassium   1 to 10 Magnasweet 110   1 to 10 Sodium Benzoate 0.5 to 4Potassium Sorbate 0.5 to 4 Water q.s. to 1-15 mL

TABLE 8 Budesonide Composition #8 Ingredient Amount (mg/mL) Amount % w/wBudesonide 0.05 0.004 Avicel RC-591 23.6 2 Dextrose 118 10 Maltodextrin(M150) 306.8 26 Disodium edetate 0.59 0.05 Citric acid 1.77 0.15 Sodiumcitrate 0.59 0.05 Polysorbate 80 0.12 0.01 Cherry Flavor 5.9 0.5Glycerin 59 5 Acesulfame potassium 5.9 0.5 Magnasweet 110 5.9 0.5 SodiumBenzoate 2.36 0.2 Potassium Sorbate 2.36 0.2 Water q.s. to 1, 2, 3, 4,5, 6, q.s. to 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 6, 7, 8, 9, 10, 12, 13,14, or 15 mL 11, 12, 13, 14, or 15 mL

TABLE 9 Budesonide Composition #9 Ingredient Amount (mg/mL) Amount % w/wBudesonide 0.2 0.17 Avicel RC-591 23.6 2 Dextrose 118 10 Maltodextrin(M150) 306.8 26 Disodium edetate 0.59 0.05 Citric acid 1.77 0.15 Sodiumcitrate 0.59 0.05 Polysorbate 80 0.12 0.01 Cherry Flavor 5.9 0.5Glycerin 59 5 Acesulfame potassium 5.9 0.5 Magnasweet 110 5.9 0.5 SodiumBenzoate 2.36 0.2 Potassium Sorbate 2.36 0.2 Water q.s. to 1, 2, 3, 4,5, 6, q.s. to 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 6, 7, 8, 9, 10, 12, 13,14, or 15 mL 11, 12, 13, 14, or 15 mL

TABLE 10 Fluticasone Propionate Composition #1 Ingredient AmountFluticasone Propionate 0.5 mg to 150 mg CMC, MCC, Carbomer, HPMC and/orHEC 0.5 g to 10 g Dextrose 0 g to 100 g Maltodextrin 0 g to 100 g EDTA(e.g., disodium edetate) 5 mg to 200 mg Citric Acid 10 mg to 1 g Citrate(e.g., sodium citrate) 10 mg to 2 g Polysorbate 80 (e.g., Tween 80) 5 mgto 100 mg Flavoring Agent optional Sweetener optional Preservativeoptional Water q.s. to 100 mL

TABLE 11 Fluticasone Propionate Composition #2 Ingredient AmountFluticasone Propionate 0.5 mg to 150 mg CMC, MCC, Carbomer, HPMC and/orHEC 0 g to 10 g Dextrose 1 g to 100 g Maltodextrin 0 g to 100 g EDTA(e.g., disodium edetate) 5 mg to 200 mg Citric Acid 10 mg to 1 g Citrate(e.g., sodium citrate) 10 mg to 2 g Polysorbate 80 (e.g., Tween 80) 5 mgto 100 mg Flavoring Agent optional Sweetener optional Preservativeoptional Water q.s. to 100 mL

TABLE 12 Fluticasone Propionate Composition #3 Ingredient AmountFluticasone Propionate 0.5 mg to 150 mg CMC, MCC, Carbomer, HPMC and/orHEC 0 g to 10 g Dextrose 0 g to 100 g Maltodextrin 1 g to 100 g EDTA(e.g., disodium edetate) 5 mg to 200 mg Citric Acid 10 mg to 1 g Citrate(e.g., sodium citrate) 10 mg to 2 g Polysorbate 80 (e.g., Tween 80) 5 mgto 100 mg Flavoring Agent optional Sweetener optional Preservativeoptional Water q.s. to 100 mL

Diseases

In some embodiments, provided herein are methods of treating,preventing, or alleviating inflammation or symptoms associated withinflammation of the gastrointestinal tract, e.g., the esophagus. Inspecific embodiments, the method provided herein is a method of reducingor alleviating symptoms of inflammation of the gastrointestinal tract.In more specific embodiments, the inflammation of the gastrointestinaltract is eosinophilic esophagitis (EoE). In some embodiments, the methodprovided herein is a method of treating inflammation associated witheosinophilic esophagitis (EoE). In certain embodiments, the methodprovided herein is a method of treating dysphagia associated witheosinophilic esophagitis (EoE). In some embodiments, the method providedherein is a method of treating inflammation and dysphagia associatedwith eosinophilic esophagitis (EoE). In certain embodiments, providedherein are methods of treating diseases or conditions of thegastrointestinal tract (e.g., a disease or condition of the uppergastrointestinal tract, including a disease or condition of theesophagus), by administering a composition described herein.

In some embodiments, administration of the composition described hereintreats, prevents, or alleviates inflammation or symptoms associated withthe inflammatory disease or condition. Diseases or conditions of thegastrointestinal tract include, by way of non-limiting example, anychronic inflammatory or malignant state that involves thegastrointestinal tract (e.g., the upper gastrointestinal tract,esophagus, stomach and/or digestive tract) and responds to steroidtherapy. In certain instances) the diseases or conditions treated by thecompositions described herein include diseases or conditions of theupper gastrointestinal tract (including pre-colonic disease anddisorders), the esophagus, the stomach, and/or the digestive tract. Themethods of the present invention are useful, for example, for treating,preventing and alleviating the inflammation associated with or symptomsof eosinophilic esophagitis, inflammatory bowel diseases involving theesophagus, Crohn's disease, acute esophageal inflammation secondary tocaustic/irritant ingestion, persistent/recurrent esophageal stricturessecondary to caustic/irritant, conditions due to ingestion, systemicdiseases, congenital diseases, post-surgery inflammation, and gastroenteritis. The methods of the present invention are also useful, forexample, for treating, preventing and alleviating inflammationassociated with or symptoms of gastroesophageal reflux disease (GERD),nonerosive reflux disease (NERD), Barrett's Esophagus, and/or erosiveesophagitis.

It will be appreciated that reference herein to treatment extends toprophylaxis as well as the treatment of inflammation or other symptoms.

In certain embodiments, provided herein is a method of treating,preventing or alleviating inflammation of the gastrointestinal tract,including, by way of non-limiting example, the esophagus, stomach and/ordigestive tract, in an individual comprising orally administering tosaid individual any of the compositions described herein. In certainembodiments, the oral dosage form comprises a liquid vehicle and isformulated as, e.g., a slurry, suspension, syrup, dispersion, solution,etc.

In one aspect, a patient is administered a corticosteroid such as, forexample, budesonide or fluticasone propionate.

In some embodiments, the inflammation treated by the methods andcompositions described herein is associated with eosinophilicinflammation and/or neutrophilic inflammation. In some embodiments,individuals (e.g., patients) to be treated with compositions describedherein include those that have been diagnosed with eosinophilicesophagitis, an inflammatory bowel disease involving the esophagus,Crohn's disease, celiac disease, proximal gastrointestinal pathology(e.g., in individuals suffering from hypofunctioning gallbladder),eosinophilic gastrointestinal inflammation, celiac disease, eosinophilicduodenitis, duodenal eosinophilia, functional dyspepsia, intermediateesophagitis, epithelial hyperplasia, basal cell hyperplasia, elongatedpapillae, dilated vessels in papillae, fungal esophagitis (e.g.,Candida, turolopsis, histoplasma Aspergillus, etc.), viral esophagitis(e.g., HSV, CMV, V2V), bacterial esophagitis (e.g., tuberculosis,actinomycosis, syphlis), corrosive esophagitis, radiation esophagitis,chemotherapy esophagitis, graft vs. host disease, a skin disease withesophageal involvement (e.g., bullous pemphigoid, pemphigus vulgaris,epidermolysis bollosa, Stevens-Johnson syndrome), Behçet's disease,sarcoidosis, idiopathic esophagitis, eosinophilic gastritis, Menetrier'sdisease, parasitic gastritis, lymphocytic esophagitis, inflammatorybowel disease-associated esophagitis, parasitic gastritis, esophagealinflammation secondary to caustic/irritant ingestion,persistent/recurrent esophageal strictures of any cause and includingcaustic/irritant ingestion, pill-induced esophagitis, systemic diseases,congenital diseases, post-surgery inflammation, or gastro enteritis. Inone non-limiting example, the patient has eosinophilic esophagitis. Insome embodiments, individuals (e.g., patients) to be treated with thecompositions described herein include those that have been diagnosedwith Barrett's Esophagus, gastroesophageal reflux disease (GERD),nonerosive reflux disease (NERD) and/or erosive esophagitis. In someembodiments, the patient is an adult. In other embodiments, the patientis a child or infant. In various aspects, a patient is a child or infantless than 16 years old, less than 12 years old, less than 8 years old,less than 6 years old, less than 4 years old or less than 2 years old.

In some embodiments, a composition is in a unit dose formulation fororal administration of a patient. In some embodiments, a unit dose ofthe corticosteroid is administered from a metered dose device. In someembodiments, the metered dose device delivers a metered unit dose of acomposition described herein to the mouth or throat of an individual inneed thereof. In certain embodiments, the metered dose device is ametered inhaler, which is utilized to administer a metered unit dose tothe mouth or throat of an individual (the individual swallows ratherthan inhales the metered unit dose). In certain embodiments, a metereddose device dispenses a metered unit dose of a composition describedherein into a receptacle (e.g., a cup), which is then utilized to orallyadminister the metered unit dose to the mouth or throat. In certainaspects, about 0.01 mg to about 20 mg, about 0.01 mg to about 15 mg, orabout 0.01 mg to about 10 mg (e.g., about 0.1-10 mg, about 0.25-5 mg,about 0.3-4 mg, about 0.25-2.5 mg, about 1-2 mg or about 2-3 mg)corticosteroid per day or per dose is administered to an individual. Insome embodiments, the corticosteroid is present in a composition or aunit dose of a composition described herein in an amount of from about0.01 mg to about 10 mg (e.g., about 0.1-10 mg, about 0.25-5 mg, about0.25-2.5 mg, about 1-2 mg or about 2-3 mg). In some embodiments, theamount of corticosteroid administered daily or in a unit dose is betweenabout 0.5 mg and about 3 mg. In other embodiments, the amount ofcorticosteroid present in a unit dose or administered daily is betweenabout 1 and about 3 mg, or between about 1 and about 2 mg, or betweenabout 2 and about 3 mg.

The entirety of each patent, patent application, publication anddocument referenced herein is hereby incorporated by reference. Citationof the above patents, patent applications, publications and documents isnot an admission that any of the foregoing is pertinent prior art, nordoes it constitute any admission as to the contents or date of thesepublications or documents.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andsystems similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the methods, devices,and materials are now described. All publications mentioned herein areincorporated herein by reference for the purpose of describing anddisclosing the processes, systems, and methodologies which are reportedin the publications which might be used in connection with theinvention. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

Modifications may be made to the foregoing without departing from thebasic aspects of the invention. Although the invention has beendescribed in substantial detail with reference to one or more specificembodiments, those of ordinary skill in the art will recognize thatchanges may be made to the embodiments specifically disclosed in thisapplication, and yet these modifications and improvements are within thescope and spirit of the invention. The invention illustrativelydescribed herein suitably may be practiced in the absence of anyelement(s) not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof”, and “consisting of” may be replaced with either of the other twoterms. Thus, the terms and expressions which have been employed are usedas terms of description and not of limitation, equivalents of thefeatures shown and described, or portions thereof, are not excluded, andit is recognized that various modifications are possible within thescope of the invention.

In some embodiments, provided herein is a multiple unit containercomprising about 2 to about 180, about 10 to about 60, about 14, orabout 30 unit doses of any pharmaceutical composition described herein.In more specific embodiments, each dose comprises about 1 mL to about 25mL, about 1 mL to about 20 mL, about 7 mL to about 25 mL, about 10 toabout 20 mL, about 15 mL, about 20 mL, about 3 to about 7 mL, about 5nm, about 8 mL to about 12 mL, or about 10 mL. In still more specificembodiments, each dose comprises about 0.1 to about 20 mg, about 0.1 toabout 10 mg, about 0.1 to about 7.5 mg, about 0.1 to about 5 mg, about0.3 to about 4 mg, about 0.25 to about 2.5 mg, about 0.3 mg to about 2mg, about 0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about0.375 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg orabout 2 mg of corticosteroid. In certain embodiments, provided herein isa multiple unit container comprising about 10 mL to about 1500 mL, about50 mL to about 600 mL, about 150 mL, about 300 mL, about 600 mL, orabout 1,200 mL of any pharmaceutical composition described herein. Inspecific embodiments, the multidose container comprises about 330 mL orabout 55 mL of a composition described herein. In some embodiments, akit provided herein comprises any multidose container as describedherein, a pharmaceutical composition as described herein (e.g., in avolume described), and a delivery device (e.g., a syringe, a cup, aspoon, or the like). In specific embodiments, the delivery device isincorporated into the container (e.g., an nebulizer, a aerosolizer, apump, or the like). In certain embodiments, the pharmaceuticalcomposition contained within any of the multiple unit containersdescribed herein is physically and chemically stable.

In certain aspects, about 0.1 mg to about 20 mg, about 0.25 mg to about20 mg, about 0.25 mg to about 15 mg, about 0.25 mg to about 10 mg, orabout 0.25 mg to about 5 mg (e.g., about 0.1 to about 5 mg, about 0.3 mgto about 4 mg, about 0.25 to about 2.5 mg, about 0.3 mg to about 2 mg,about 0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about 0.375mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg or about 2mg) corticosteroid per day is administered to a patient. In someembodiments, the corticosteroid is present in a unit dose in an amountof between about 0.25 mg and about 5 mg. In some embodiments, the amountof corticosteroid administered daily or in a unit dose is between about0.3 mg and about 4 mg. In certain embodiments, the amount ofcorticosteroid administered daily or in a unit dose is between about 0.5mg and about 3 mg. In other embodiments, the amount of corticosteroidpresent in a unit dose or administered daily is between about 1 andabout 3 mg, or between about 1 and about 2 mg, or between about 2 andabout 3 mg.

In some embodiments, any composition or formulation described herein isstable. In specific embodiments, the composition is chemically andphysically stable. In certain embodiments, chemical stability isevidenced by a composition that comprises at least 80%, 90%, 95%, 98%,or 99% of the initial amount or label amount of corticosteroid and/oroptional additional active agent therein for, by way of non-limitingexample, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year,2 years, or for the duration of the shelf life. In some embodiments,physical stability is evidenced by a pharmaceutical composition that isable to substantially obtain uniformity, remain substantially uniform(e.g., for at least 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3months, 6 months, 1 year, 2 years, etc.), or substantially regainuniformity (e.g., via mild or moderate agitation after being undisturbedfor 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6months, 1 year, 2 years, etc.). In certain embodiments, physicalstability is evidenced by a composition that comprises at least 80%,90%, 95%, 98%, or 99% of the initial amount or label amount ofcorticosteroid and/or optional additional active agent therein for, byway of non-limiting example, 2 days, 1 week, 2 weeks, 3 weeks, 1 month,3 months, 6 months, 1 year, 2 years, or for the duration of the shelflife. In certain embodiments, uniformity as described herein isevidenced by the uniformity of the dispersion of the corticosteroidparticles throughout the pharmaceutical composition, the uniformity ofthe dispersed mass of corticosteroid throughout the pharmaceuticalcomposition, the uniformity of the concentration of one or more of thecomponents in the composition throughout the pharmaceutical composition,and the like. In certain embodiments, mild or moderate agitationincludes, by way of non-limiting example, shaking, shaking well,swirling, gentle swirling, and the like. In some embodiments, mild ormoderate agitation includes agitation without a special apparatus. Insome embodiments, uniformity of the pharmaceutical composition refers todose uniformity (e.g., each dose delivered or withdrawn from thecomposition comprises a substantially similar amount of corticosteroid),or the concentration of corticosteroid in at least some or all of thedoses from the multiple dose formulations are substantially similar. Incertain embodiments, substantially similar includes, e.g., within 20%,15%, 10%, 7%, 5%, 3%, 2%, or 1%.

In some embodiments, the dose or volume of a composition administeredherein is adjusted based on the efficacy of treatment. In certainembodiments, a diagnosis of eosinophilic esophagitis is achieved byadministering a composition described herein and determining theefficacy of the treatment. In certain embodiments, a compositiondescribed herein and separately determined to be effective in treatingeosinophilic esophagitis is utilized. Efficacy of treatment can bedetermined in any suitable manner including, e.g., symptom scoreassessment, gastrointestinoscopy (e.g., esophagogastroduodenoscopy),gastrointestinal (e.g., esophageal) biopsy, histological evaluation, ora combination thereof. Processes of diagnosing eosinophilic esophagitisand/or determining efficacy of treatment include any suitable processincluding, by way of non-limiting example, processes as set forth inAceves et al, J Allergy Clin Immunol, February 2008; abstract 270, orAceves et al, Am J Gastroenterol., October 2007, 102 (10):2271-9, bothof which are incorporated herein in their entirety.

In some embodiments, a process for determining efficacy of a treatment(e.g., for eosinophilic esophagitis) described herein is a clinicalsymptom score assessment comprising (i) administering a compositiondescribed herein to an individual diagnosed with or suspected of havingeosinophilic esophagitis; and (ii) evaluating one or more symptom of theindividual. Symptoms that are optionally scored include, by way ofnon-limiting example, nausea, vomiting, pain, and heartburn. Total scoreor change in score is optionally utilized to diagnose a disorder and/ordetermine efficacy of treatment.

In certain embodiments, a process for determining efficacy of atreatment described herein comprises (i) administering a compositiondescribed herein to an individual diagnosed with or suspected ofsuffering from inflammation of the gastrointestinal tract (e.g.,eosinophilic esophagitis) and/or symptoms associated therewith; (ii)endoscoping the gastrointestinal surface of the individual; (iii)biopsying the gastrointestinal surface tissue; and (iv) evaluating thebiopsied tissue and optionally determining an endoscopy score of thetissues biopsied. In specific embodiments, the process further comprisescomparing the evaluated biopsied tissue and/or the endoscopy scoreobtained prior to administration of the composition to the biopsiedtissue and/or endoscopy score subsequent to administration of thecomposition.

In some embodiments, provided herein is a process of diagnosing anindividual with gastrointestinal inflammation by (i) detecting and/ormeasuring symptoms of the individual prior to administering to theindividual a composition described herein; (ii) administering to theindividual any composition described herein; (iii) detecting and/ormeasuring symptoms of the individual following administration of thecomposition; and (iv) comparing the symptoms measured or detected priorto and following administration of a composition described herein. Ifthe symptoms exhibited by the individual are reduced (e.g., by astatistically significant or clinically relevant amount), a positivediagnosis occurs. In specific embodiments, the process of diagnosing anindividual with gastrointestinal inflammation is diagnosing anindividual with eosinophilic esophagitis.

Combinations

As discussed herein, compositions and formulations described comprise atleast one corticosteroid (e.g., budesonide or fluticasone propionate).In some embodiments, a composition or formulation described hereinfurther comprises at least one additional active agent. In specificembodiments, a composition or formulation described herein comprises atherapeutically effective amount of a corticosteroid and atherapeutically effective amount of at least one additional activeagent. In some embodiments, the at least one additional active agent isan agent that treats, prevents, or alleviates the symptoms of and/orinflammation associated with inflammatory diseases involving thegastrointestinal tract (e.g., esophagus). It is to be understood that incertain instances, when the corticosteroid is combined with anadditional active agent, the therapeutically effective amount of thecorticosteroid is less than it when the additional active agent isabsent.

Furthermore, provided herein are methods of preventing or alleviatinggastrointestinal (e.g., esophageal) inflammation in an individualcomprising orally administering to the individual a corticosteroid inassociation or combination with at least one additional active agent. Incertain embodiments, the corticosteroid and the at least one additionalactive agent is in a single dosage form. In other embodiments, thecorticosteroid and the at least one additional active agent are inseparate dosage forms and are administered in any manner, including, byway of non-limiting example, simultaneously, sequentially, or atdifferent times. For example, in certain embodiments, several doses of acorticosteroid composition are administered over a period of time, afterwhich administration of the corticosteroid composition is discontinuedand administration of at least one additional active agent isadministered at least once.

In some embodiments, the at least one additional active agent utilizedin a composition, formulation or method described herein is an agentthat treats, prevents, or alleviates the symptoms of and/or inflammationassociated with inflammatory diseases involving the gastrointestinaltract (e.g., esophagus). In more specific embodiments, the at least oneadditional active agent is not a second corticosteroid. In certainembodiments, the at least one additional active agent is an acidinhibitor (e.g., an H2 antagonist and/or a PPI). In certain embodiments,the at least one additional active agent is, by way of non-limitingexample, a proton pump inhibitor (PPI), a H2 antagonist, a transientlower esophageal sphincter relaxation (TLESR)-reducing agent, aserotonergic agent/prokinetics, a potassium-competitive acid blocker(P-CAB), a mucosal protectant, a histamine H3 agonist, an anti-gastrinagent, or combinations thereof.

In certain embodiments, a patient combines treatment with a compositiondescribed herein with a treatment with another medication, and/ordietary therapy.

EXAMPLES Example 1

This example illustrates the increased interaction between a compositiondescribed herein and the esophagus when compared to a radiolabeled oralcomposition made by combining Pulmicort Respules® (4 mL) with ^(99m)Tcpertechnetate, and diluting with saline to about 7-8 mL (M0). The M0composition has a viscosity of about 1 cP at 13.2 sec⁻¹. Administered toa population of healthy individuals was a radiolabeled oral budesonidecomposition (M1). The radiolabeled budesonide composition (M1) was madein a volume of about 7-8 mL by combining Pulmicort Respules®, about 10packets of Splenda® (distributed by McNeil Nutritionals, LLC FortWashington, Pa. 19034-2299), and ^(99m)Tc pertechnetate, comprises about7% w/w maltodextrin, and has a viscosity of about 200 cP at 13.2 sec⁻¹.The radiolabeled budesonide composition (M2) was made in a volume ofabout 7-8 mL by combining Pulmicort Respules®, 70% w/w maltodextrin, and^(99m)Tc pertechnetate, having a viscosity of about 1450 cP at 13.2sec⁻¹. Also administered to a population of healthy individuals was aradiolabeled budesonide composition (Rhinocort Aqua®, M3), which has aviscosity of about 39 at 13.2 sec⁻¹. Increased interaction of thebudesonide composition was determined by measuring the amount ofradiolabel present in the esophagus following oral administration of theoral viscous budesonide composition. FIG. 1 illustrates the percentamount of composition present in the esophagus as a function of timefollowing oral administration (by measuring the amount of radiolabelpresent in the esophagus).

The area under the curve (AUCr) of the percent of the dose administeredas a function of time (% dose·time (min)) was determined from the timeof 50% swallow (i.e., 50% of the administered dose had passed from themouth), until esophageal activity had peaked and fallen to 10% of thepeak value. The area under the curve from t=0 min to t=1 min (AUC₀₋₁);and from t=0 min to t=2 min (AUC₀₋₂) was also determined. These results(including the ratio of the non-viscous sample to the viscous sample)are set forth below:

AUCr AUC₀₋₁ AUC₀₋₂ geometric geometric geometric Formulation mean ratiomean ratio mean ratio M0 3.95 5.51 6.93 M1 6.33 0.62 8.84 0.62 9.41 0.74M2 17.67 0.22 18.91 0.29 21.94 0.32 M3 9.39 0.42 11.07 0.5 14.16 0.49

Example 2

This example details the efficacy and safety of once daily and twicedaily use of budesonide in a formulation described herein in 5 mL and 7mL doses in inducing and maintaining remission of disease activity inchildren with EE. A number of children (e.g., 20 per budesonide dosefrequency, amount, and volume) are evaluated to determine the highesteosinophil count (eos/hpf) and the mean highest eosinophil count for thegroup. Evaluation of the highest eosinophil count (eos/hpf) and the meanhighest eosinophil count for the group is also determined followingtherapy. Symptom scores and mean symptom scores are also determinedbefore and after therapy.

In some instances, individuals who received previous therapy with protonpump inhibitor, elimination diet based upon skin or blood allergytesting, or elimination diet or refused elimination diet, but continuedto have ≧24 eos/hpf on esophageal biopsy are included in the review.Patients are defined as having food or aeroallergen sensitization ifRAST and/or skin prick testing are positive. No changes are made tolongstanding therapy used for treating chronic conditions such as asthmaor eczema and none of the children receive concurrent immune-modulatorytreatment.

Endoscopy is performed using the Olympus P160 endoscope (by RD) andpan-esophageal, gastric and duodenal biopsies are taken. Eosinophilicesophagitis is diagnosed when ≧24 eos/hpf are found in at least one ofthe esophageal sites biopsied. Two mucosal biopsies are taken from theproximal esophagus (3 cm below the crycopharyngeus muscle), distalesophagus (3 cm above the gastroesophageal junction (GEJ), andmid-esophagus (midpoint between the crycopharyngeus muscle and the GEJ).Biopsies are processed routinely and evaluated by a pediatricpathologist (RN). The highest number of eosinophils per ×400 high powerfield are counted. Basal zone hyperplasia (BZH) is reported when basalzone cells extend towards the luminal surface of the epithelium (>25% ofepithelial thickness).

Follow-up endoscopy with biopsies are taken after 3-4 months treatment.Counting the highest number of eos/hpf within biopsies determined theresponse to therapy and patients are categorized into responders (0-7eos/hpf), partial-responders (8-23 eos/hpf) and non-responders (≧24eos/hpf).

An EE (EoE) Endoscopy Score is devised to compare findings before andafter treatment. It is calculated from procedure reports andphotographs. Four categories, (U) pallor and diminished vascularmarkings; (2) furrowing with “thickened” mucosa; (3) white mucosalplaques; (4) concentric rings or strictures. For each category, onepoint is allocated if 1 or 2 esophageal sites are involved, and twopoints for pan-esophageal involvement. The maximum score is 8.

Patients receive a formulation described herein for between 0.25 and 2mg daily and are instructed not to ingest any solids or liquids for 30minutes afterwards. No dietary changes are made in patients already ondietary restrictions.

A modified symptom score based on children with acid-peptic disease isused routinely in the EE (EoE) clinic. The symptom categories include(1) heartburn or regurgitation; (2) abdominal pain or unexplainedirritability in younger children; (3) nausea or vomiting; (4) anorexiaor early satiety; (5) dysphagia or odynophagia, (6) nocturnal wakeningwith symptoms; (7) gastrointestinal bleeding (previous 4 months). Eachcategory scored 0-2 points with a maximum of 14 points. Zero points areawarded if the symptom is absent; one point if the symptom is mild, didnot interfere with daily activities; 2 points if the symptoms are severeenough to interrupt daily activities. Previous GI bleeding is consideredmild (1 point) if there is no associated hemodynamic compromise oranemia, and severe (2 points) if bleeds are multiple, caused anemia, orrequired blood transfusion.

All statistical analysis is carried out using NCSS Statistical SoftwarePackage. Two-tailed p values are calculated using paired t-tests tocompare the means of patient values for eos/hpf, EE (EoE) EndoscopyScores and Symptom Scores before and after budesonide therapy.Two-tailed unpaired t-tests are utilized in order to compare variablesgrouped by responders versus non-responders. Spearman's correlationcoefficients are generated using GraphPad Prism software. Results with pvalues <0.05 are considered statistically significant. Both mean andmedian statistics are generated, both are equivalent and mean statisticsare presented.

Subjects. Chart reviews are undertaken on a number of children. Allchildren have >24 eos/hpf on repeat esophageal biopsy before startingtherapy.

Treatment. Patients received the described formation for a designatedamount of time (e.g., 1 week, 2 weeks, 1 month, 2 months, 3 months, 4months, 6 months, or the like) before repeat endoscopy. Various patientsreceived budesonide in amounts ranging from 0.25 to 2 mg/day.

Histology. Before treatment the mean highest eosinophil count ismeasured for all patients, including distal, mid and proximal esophagealsites. All sites are likewise evaluated aver the designated amount oftime, and again if desired.

Upper Gastrointestinal Endoscopy. Before treatment, the mean EE (EoE)Endoscopy Score for all patients is determined. Following treatment themean EE (EoE) Endoscopy Score is repeated. Decreases in endoscopy scores(e.g., of >95%, >90%, >85%, >75%, >50%, >25%, or the like) in anindividual indicate successful treatment.

Symptom Score. Before treatment the mean symptom score for all patientsis determined. It is again determined following treatment. Decreases insymptom scores (e.g., of >95%, >90%, >85%, >75%, >50%, >25%, or thelike) in an individual indicate successful treatment (alone or incombination with the above referenced decreases in endoscopy scores).

Adults: these parameters are repeated in adults to determine efficacyand safety therein.

Example 3

This example details the efficacy and safety of once daily and twicedaily use of budesonide in a formulation described herein in inducingand maintaining remission of disease activity in individuals (childrenand/or adults) with GERD. Doses of 0-1 mg, 1-2 mg, 2-3 mg, 3-4 mg, 4-5mg, and 5-6 mg per daily dose are administered once a day, b.i.d. ort.i.d. in volumes of 3, 5, 7, 10, 12, 15, or 17.5 mL. A number ofindividuals (e.g., 20 per budesonide dose frequency, amount, and volume)are evaluated to determine the symptoms prior to therapy, during therapyand following therapy. Administration is conducted for 7 days, 14 days,and 28 days. Primary Outcome Measures include complete resolution ofheartburn and regurgitation (e.g., no more than one day with either mildheartburn or regurgitation over the seven days prior to the assessmenttime-point). Secondary Outcome Measures include: Number of days withheartburn (daytime and night-time); Number of days with regurgitation(daytime and night-time); Number of heartburn and regurgitation-freedays (24 hrs); Composite score of heartburn and regurgitation frequencyand severity; Time to resolution of symptoms of heartburn/regurgitation;Severity of additional GERD symptoms; Quality of Life (assessed usingPAGI-QOL to PGIC (Patient Global Impression of Change); Completeresolution of heartburn; Complete resolution of regurgitation; Averageseverity of heartburn (daytime and night-time); Average severity ofregurgitation (daytime and night-time). These symptoms are scored (e.g.,assigning a 3 to the most severe symptoms and a 0 to a lack of symptoms)and utilized to determine the efficacy of the treatment.

While certain embodiments have been shown and described herein, it willbe apparent to those skilled in the art that such embodiments areprovided by way of example only. Numerous variations, changes, andsubstitutions will now occur to those skilled in the art and areconsidered to be within the scope of the disclosure herein. It should beunderstood that various alternatives to the embodiments of the inventiondescribed herein may be employed in practicing the invention. It isintended that the following claims define the scope of the invention andthat methods and structures within the scope of these claims and theirequivalents be covered thereby.

References

1. Liacouras C A, Ruchelli E. Eosinophilic esophagitis. Cuff. Opin.Pediatr. 2004; 16:560-6.

2. Kelly K J, Lazenby A J, Rowe P C, et al. Eosinophilic esophagitisattributed to gastroesophageal reflux: improvement with an aminoacid-based formula. Gastroenterology 1995; 109: 1503-12.

3. Fogg M I, Ruchelh E, Spergel J M. Pollen and eosinophilicesophagitis. J. Allergy Clin. Immunol. 2003; 112:796-7.

4. Mishra A, Hogan S P, Brandt E B, Rothenberg M E. An etiological rolefor aeroallergens and eosinophils in experimental esophagitis. J. Clin.Invest. 2001; 107:83-90.

5. Spergel J M, Beausoleil J L, Mascarenhas M, Liacouras C A. The use ofskin prick tests and patch tests to identify causative foods ineosinophilic esophagitis. J. Allergy Clin. Immunol. 2002; 109:363-8.

6. Ruchelli E, Wenner W, Voytek T, et al. Severity of esophagealeosinophilia predicts response to conventional gastroesophageal refluxtherapy. Pediatr. Dev. Pathol. 1999; 2:15-8.

7. Steiner S J, Gupta S K, Croffie J M, Fitzgerald J F. Correlationbetween number of eosinophils and reflux index on same day esophagealbiopsy and 24 hour esophageal pH monitoring. Am. J. Gastroenterol. 2004;99:801-5.

8. Orenstein S R, Shalaby T M, Di Lorenzo C, et al. The spectrum ofpediatric eosinophilic esophagitis beyond infancy: a clinical series of30 children. Am. J. Gastroenterol. 2000; 95:1422-30.

9. Rothenberg M E, Mishra A, Collins M H, Putnam P E. Pathogenesis andclinical features of eosinophilic esophagitis. J. Allergy Clin. Immunol.2001; 108:891-4.

10. Ravelli A M, Villanacci V, Ruzzenenti N, et al. DilatedIntercellular Spaces: A Major Morphological Feature of Esophagitis. J.Pediatr. Gastroenterol. Nutr. 2006; 42:510-515.

11. Steiner S J, Kernek K M, Fitzgerald J F. Severity of Basal CellHyperplasia Differs in Reflux Versus Eosinophilic Esophagitis. J.Pediatr. Gastroenterol. Nutr. 2006; 42:506-509.

12. Mueller S, Aigner T, Neureiter D, Stolte M. Eosinophil infiltrationand degranulation in oesophageal mucosa from adult patients witheosinophilic oesophagitis: a retrospective comparative study onpathologic biopsy. J. Clin. Pathol. 2006; 59:1175-80.

13. Croese J, Fairley S K, Masson J W, et al. Clinical and endoscopicfeatures of eosinophilic esophagitis in adults. Gastrointest. Endosc.2003; 58:516-22.

14. Aceves S, Newbury, R O, Dohil R, Schwimmer J, Bastian J.Distinguishing Eosinophilic Esophagitis in pediatric patients: clinical,endoscopic, and histologic features of an emerging disorder. Journal ofClinical Gastroenterology 2006; 41 (3):252-6.

15. Straumann A, Simon H U. Eosinophilic esophagitis: escalatingepidemiology? J. Allergy Clin. Immunol. 2005; 115:418-9.

16. Cherian S, Smith N M, Forbes D A. Rapidly increasing prevalence ofeosinophilic oesophagitis in Western Australia. Arch. Dis. Child 2006;91:1000-4.

17. Sant'Anna A M, Rolland S, Fournet J C, et al. EosinophilicEsophagitis in Children: Symptoms, Histology and pH Probe Results. J.Pediatr. Gastroenterol. Nutr. 2004; 39:373-377.

18. Potter J W, Sacian K, Staff D, et al. Eosinophilic esophagitis inadults: an emerging problem with unique esophageal features.Gastrointest. Endosc. 2004; 59:355-61.

19. Parfitt J R, Gregor J C, Suskin N G, et al. Eosinophilic esophagitisin adults: distinguishing features from gastroesophageal reflux disease:a study of 41 patients. Mod. Pathol. 2006; 19:90-6.

20. Desai T K, Stecevic V, Chang C H, et al. Association of eosinophilicinflammation with esophageal food impaction in adults. Gastrointest.Endosc. 2005; 61:795-801.

21. Straumanm A, Spichtin H P, Grize L, et al. Natural history ofprimary eosinophilic esophagitis: a follow-up of 30 adult patients forup to 11.5 years. Gastroenterology 2003; 125:1660-9.

22. Spergel J M, Andrews T, Brown-Whitehorn T F, et al. Treatment ofeosinophilic esophagitis with specific food elimination diet directed bya combination of skin prick and patch tests. Ann. Allergy AsthmaImmunol. 2005; 95:336-43.

23. Kagalwalla A F, Sentongo T A, Ritz S, et al. Effect of six-foodelimination diet on clinical and histologic outcomes in eosinophilicesophagitis. Clin. Gastroenterol. Hepatol. 2006; 4:1097-102.

24. Markowitz J E, Spergel J M, Ruchelli E, Liacouras C A. Elementaldiet is an effective treatment for eosinophilic esophagitis in childrenand adolescents. Am. J. Gastroenterol. 2003; 98:777-82.

25. Liacouras C A, Wenner W J, Brown K, Ruchelli E. Primary eosinophilicesophagitis in children: successful treatment with oral corticosteroids.J. Pediatr. Gastroenterol. Nutr. 1998; 26:380-5.

26. Teitelbaum J E, Fox V L, Twarog F J, et al. Eosinophilic esophagitisin children: immunopathological analysis and response to fluticasonepropionate. Gastroenterology 2002; 122:1216-25.

27. Faubion W A, Jr., Perrault J, Burgart L J, et al. Treatment ofeosinophilic esophagitis with inhaled corticosteroids. J. Pediatr.Gastroenterol. Nutr. 1998; 27:90-3.

28. Aceves S S, Dohil R, Newbury R O, Bastian J F. Topical viscousbudesonide suspension for treatment of eosinophilic esophagitis. J.Allergy Clin. Immunol. 2005; 116:705-6.

29. Noel R J, Putnam P E, Collins M H, et al. Clinical andimmunopathologic effects of swallowed fluticasone for eosinophilicesophagitis. Clin. Gastroenterol. Hepatol. 2004; 2:568-75.

30. Remedios M, Campbell C, Jones D M, Kerlin P. Eosinophilicesophagitis in adults: clinical, endoscopic, histologic findings, andresponse to treatment with fluticasone propionate. Gastrointest. Endosc.2006; 63:3-12.

31. Dohil R, Newbury R O, Sellers Z M, et al. The evaluation andtreatment of gastrointestinal disease in children with cystinosisreceiving cysteamine. J. Pediatr. 2003; 14:224-30.

32. Cheung K M, Oliver M R, Cameron D J, et al. Esophageal eosinophiliain children with dysphagia. J. Pediatr. Gastroenterol. Nutr. 2003;37:498-503.

33. Fox V L, Nurko S, Furuta G T. Eosinophilic esophagitis: it's notjust kid's stuff. Gastrointest. Endosc. 2002; 56:260-70

34. Budin C, Villard-Truc F, Rivet C, et al. [Eosinophilic esophagitis:3 case reports]. Gastroenterol. Clin. Biol. 2005; 29:73-5.

35. Noel R J, Putnam P E, Rothenberg M E. Eosinophilic esophagitis. N.Engl. J. Med. 2004; 351:940-1.

36. Guajardo J R, Plotnick L M, Fende J M, et al. Eosinophil-associatedgastrointestinal disorders: a world-wide-web based registry. J. Pediatr.2002; 141:576-81.

37. Liacouras C A, Spergel J M, Ruchelli E, et al. Eosinophilicesophagitis: a 10-year experience in 381 children. Clin. Gastroenterol.Hepatol. 2005; 3:1198-206.

38. Liacouras C A. Eosinophilic esophagitis: treatment in 2005. Curr.Opin. Gastroenterol. 2006; 22:147-152.

39. Spergel J M. Eosinophilic esophagitis in adults and children:evidence for a food allergy component in many patients. Curr. Opin.Allergy Clin. Immunol. 2007; 7:274-8.

40, Plaza-Martin, A M, Jimenez-Feijoo R, Andaluz C, Giner-Munoz M T,Martin-Mateos M A, Piquer-Gibert M, Sierra-Martinez J I.Polysensitization to aeroallergens and food in eosinophilic esophagitisin a pediatric population. Alergol. Immunopathol. 2007; 35:35-7.

41. Nicolazzo, J A, Reed, B L, Finnin, B C. Buccal penetrationenhancers—how do they really work? J. Controlled Release 2005; 105:1-15.

42. Furuta, G T, Liacouras, C A, Collins, M H, Sandeep, K G, Justinich,C, Putnam, P E, Bonis, P, Hassall, E, Straumann, A, Rothenberg, M E.Eosiniophilic esophagitis in children and adults: A systematic reviewand consensus recommendations for diagnosis and treatment.Gastroenterology 2007; 133:1342-1363.

43. Aceves, S S, Bastian J F, Newbury, R O, Dohil, R. Oral viscousbudesonide: A potential new therapy for eosinophilic esophagitis. Amer.Journal of Gastroenterology 2007; 102:1-9.

44. Rothenberg M E. Eosinophilic gastrointestinal disorders. J. AllergyClin. Immunol. 2004; 113:11-28.

45. Garrett J K, Jameson S C, Thomson B, Collins M H, Wagoner L E,Freese, D K, et al. Anti-interleukin-5 (mepolizumab) therapy forhypereosinophilic syndromes. J. Allergy Clin. Immunol. 2004; 113:115-9.

What is claimed is:
 1. A method of treating or alleviating esophagealinflammation or symptoms of esophageal inflammation in an individualcomprising orally administering to said individual a stable oralpharmaceutical composition comprising a topically active corticosteroid,a liquid vehicle and a mucoadhesive agent that increases the interactionof the composition with an esophageal surface, wherein the compositionis chemically and physically stable, wherein the composition remainssubstantially uniform for at least 1 day; and wherein the individual hasbeen diagnosed with Barrett's Esophagus, gastroesophageal reflux disease(GERD), nonerosive reflux disease (NERD), or erosive esophagitis.